Cancer-associated fibroblasts (CAFs) are a major component of the tumor microenvironment (TME) and play a crucial role in tumor progression. The biological properties of tumors, such as drug resistance, vascularization, immunosuppression, and metastasis are closely associated with CAFs. During tumor development, CAFs contribute to tumor progression by remodeling the extracellular matrix (ECM), inhibiting immune cell function, promoting angiogenesis, and facilitating tumor cell growth, invasion, and metastasis. Studies have shown that CAFs can promote endothelial cell proliferation by directly secreting cytokines such as vascular endothelial growth factor (VEGF) and fibroblast Growth Factor (FGF), as well as through exosomes. CAFs also secrete the chemokine stromal cell-derived factor 1 (SDF-1) to recruit endothelial progenitor cells (EPCs) into the peripheral blood and guide their migration to the tumor periphery. Additionally, CAFs can induce tumor cells to transform into "endothelial cells" that participate in vascular wall formation. However, the precise mechanisms remain to be further investigated. Due to their widespread presence in various solid tumors and their tumor-promoting function, CAFs are emerging as therapeutic targets. In this review, we summarize the specific mechanisms through which CAFs promote angiogenesis and outline current therapeutic strategies targeting CAF-induced vascularization, ongoing clinical trials targeting CAFs, and discuss potential future treatment approaches. We hope this will contribute to the advancement of CAF-targeted tumor treatment strategies.

This review examines the molecular mechanisms driving structural damage in Spondyloarthritis (SpA), a chronic inflammatory condition characterized by new bone formation that can lead to partial or complete spinal ankylosis. We explore the complex interplay between inflammation, mechanical stress, and bone metabolism in SpA, focusing on key signaling pathways and cytokines that contribute to disease progression. The review analyzes both structural and inflammatory aspects, particularly the role of enthesis biology and the impact of mechanical factors. Additionally, we assess how current therapeutic approaches, including biologic treatments targeting specific inflammatory pathways such as tumor necrosis factor inhibitors, affect disease progression. While these treatments can reduce inflammation and manage clinical symptoms, their limited ability to completely prevent new bone formation highlights the complexity of the underlying pathological processes. We also evaluate emerging therapeutic strategies targeting specific molecular pathways involved in bone formation. Understanding these intricate molecular mechanisms and their interactions is crucial for developing more effective targeted therapies that could potentially not only manage symptoms but also prevent or reverse structural damage in SpA patients.

The cardiovascular system is the first functional organ system to develop in the vertebrate embryo. The primitive heart and primitive vascular plexus are formed through vasculogenesis and thereafter through angiogenesis. After the establishment of new connections within the vascular network, a pruning and remodeling process occurs after which some branches are stabilized, whereas others regress. The aim of this article is to describe the most common pruning and remodeling forms, which take place during organogenesis in the experimental and human systems.

Angiogenesis plays an important role in tumour growth and metastasis. Targeting tumour vascular endothelial cells to inhibit tumour angiogenesis and thus block tumour blood and nutrition supply is the current research focus on anti-tumour growth and metastasis. Vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor 2 (VEGFR-2) signal pathway regulates the proliferation, migration, survival and angiogenesis of vascular endothelial cells, which is abnormally activated in different tumours. Studies have confirmed that inhibiting VEGF/VEGFR-2 signalling pathway can produce anti-tumour effect. Nowadays, anti-angiogenesis therapy targeting VEGF/VEGFR-2 inhibition has become the most effective clinical strategy for cancer treatment. Therefore, a variety of VEGF/VEGFR-2 inhibitors with different structures have been developed. A few selectively inhibit VEGF to block the activation of VEGFR-2 pathway, while the majority selectively inhibit VEGFR-2 as multi-target inhibitors. Based on the classification of dominant skeletons, this paper briefly analyzes the biological activity, clinical research process and structure-activity relationship of the representative small molecule inhibitors of VEGF/VEGFR-2.

Alpha-fetoprotein (AFP) is a well-known biomarker for liver cancer, and its clinical utility is widely recognized. Recent studies have revealed that AFP plays a multifaceted role in various malignant tumors, including liver cancer. This suggests that AFP is not merely a biomarker but also contributes significantly to the complex process of tumor formation, emphasizing the importance of targeting AFP in therapeutic approaches. Consequently, innovative research and development are essential to overcome the current limitations of AFP-targeted therapies, enhance treatment efficacy, and minimize side effects. This review explores the role of AFP in cancer development and progression, highlights the biological functions of AFP and related pathways, and discusses the clinical implications of AFP-targeted therapies. Ongoing research on AFP will significantly contribute to our understanding of the biological mechanisms of cancer and aid in developing effective and safe treatments. Ultimately, advancements in AFP-targeted therapeutic approaches are expected to play a crucial role in the future of cancer management.

Drug delivery to solid tumors is challenged by multiple physiological barriers arising from the tumor microenvironment, including dense extracellular matrix, cellular heterogeneity, hypoxic gradients, and elevated interstitial fluid pressure. These features hinder the uniform distribution and accumulation of therapeutics, reducing treatment efficacy. Despite their widespread use, conventional two-dimensional monolayer cultures fail to reproduce these complexities, contributing to the poor translational predictability of many preclinical candidates. Three-dimensional multicellular tumor spheroids have emerged as more representative in vitro models that capture essential features of tumor architecture, stromal interactions, and microenvironmental resistance mechanisms. Spheroids exhibit spatially organized regions of proliferation, quiescence, and hypoxia, and can incorporate non-tumor cells to mimic tumor-stroma crosstalk. Advances in spheroid analysis now enable detailed evaluation of drug penetration, cellular migration, cytotoxic response, and molecular gradients using techniques such as optical and confocal imaging, large-particle flow cytometry, biochemical viability assays, and microfluidic integration. By combining physiological relevance with analytical accessibility, spheroid models support mechanistic studies of drug transport and efficacy under tumor-like conditions. Their adoption into routine preclinical workflows has the potential to improve translational accuracy while reducing reliance on animal models.

We previously reported that a vascular endothelial stem cell population resides in pre-existing blood vessels in mice and may contribute to vascular endothelial cells in liver injury or hind limb ischemia models in the long-term. However, whether such stem cells exist in humans and can differentiate specifically into vascular endothelial cells have not been determined. We hypothesized that CD157+ vascular endothelial cells in humans may also possess high angiogenic potential.

First, human-derived induced pluripotent stem cells were differentiated into vascular endothelial cells and the expression of CD157 was monitored during the differentiation process. We found that CD157 emerged 11 days after the induction of differentiation, peaked at 14 days, and then declined by 24 days. We also evaluated blood vessel formation by 14- and 24-day-old vascular endothelial cells.

It was found that 14-day-old cells, when CD157 expression was at its peak, formed more blood vessels than 24-day-old cells.

These results suggest that vascular endothelial cells expressing CD157 have high angiogenic potential and may exist as vascular endothelial stem cells.

Cerebrovascular and cardiovascular diseases are pathophysiologically interconnected. In the past, researchers have mainly focused on developing one herbal medicine treatment. Single herb often fails to address the multifactorial pathology of these diseases. The pathogenesis and progression of the disease are complex, making the therapeutic effect of a single herb potentially limiting. Traditional Chinese medicine emphasizes herb pairs, which enhance therapeutic efficacy through synergistic interactions.

This review focused on the mechanisms and potential clinical applications of Chinese herb pairs such as Astragali Radix-Carthami Flos, Salviae Miltiorrhizae Radix-Puerariae Lobatae Radix, Salviae Miltiorrhizae Radix-Chuanxiong Rhizoma, Salviae Miltiorrhizae Radix-Notoginseng Radix, Salviae Miltiorrhizae Radix-Carthami Flos, Astragali Radix-Angelicae Sinensis Radix, Notoginseng Radix-Carthami Flos, and Astragali Radix-Salviae Miltiorrhizae Radix, as well as provided a scientific basis for clinical applications of Chinese herb pairs.

A systematic search and collection of studies on Chinese herb pairs in cardiovascular and cerebrovascular diseases was carried out using electronic databases such as PubMed, CNKI, Wan Fang Database, Baidu Scholar, and Web of Science. The keywords searched included Chinese herb pairs, cardiovascular disease, cerebrovascular disease, Astragali Radix, Salviae Miltiorrhizae Radix, Angelicae Sinensis Radix, Carthami Flos, Notoginseng Radix, and so on.

Studies revealed that the Chinese herb pairs had more beneficial effects than single herb and demonstrated a variety of roles in cardiovascular and cerebrovascular diseases. Preclinical studies indicated that Chinese herb pairs are more effective than single herb in treating cardiovascular and cerebrovascular diseases by modulating disease-related pathways and molecular targets. Further research is needed to fully explore their potential. The review also outlined the potential clinical applications of these Chinese herb pairs, highlighting their safety and efficacy.

Chinese herb pairs showed good promise as an alternative therapy for cardiovascular and cerebrovascular diseases due to their multi-component and multi-target characteristics. Consequently, further research was necessary to fully explore the potential of Chinese herb pairs in treating cardiovascular and cerebrovascular diseases, based on the current data.

This study aims to evaluate and compare the effect of fibroblastic growth factor 2 (FGF-2) and photobiomodulation, solely or in combination, in angiogenic differentiation of human periodontal ligament stem cells (hPDLSCs). The study comprises the following groups: control group (hPDLSCs only), FGF-2 (50 ng/mL) group, two photobiomodulation groups with a 4 J/cm2 energy density of 808 nm diode laser (1-Session or 2-Session), and two groups with the combination of each 1-Session or 2-Session photobiomodulation with FGF-2 (50 ng/mL). The 4',6-diamidino-2-phenylindole (DAPI) staining, and Methyl Thiazolyl Tetrazolium (MTT) assay were undertaken on days 2, 4, and 6. Quantitative Real-time Polymerase Chain Reaction (RT-qPCR) analysis on days 2, 4, 6, 8, and 11 was conducted to investigate VEGF-A and ANG-I genes. Coherently, the results of the DAPI and MTT showed the Laser (2-Session) group had higher cell viability than others on day 6. All groups demonstrated a growth pattern in the expression of VEGF-A and ANG-I from day 2 to 8 and, afterward, a significant downgrowth to day 11 (p < 0.05). The most amounts of expression of VEGF-A and ANG-I on day 8 were seen in the Laser (2-Session) group. Two-time application of photobiomodulation using a diode laser with 808 nm wavelength after 2 and 4 days of cell seeding can be associated with higher cell viability and angiogenic differentiation of hPDLSCs compared to the one-time application of photobiomodulation and administration of FGF-2.

Organoids provide 3D structures that replicate native tissues in biomedical research. The development of vascular networks within organoids enables oxygen and nutrient delivery while facilitating metabolic waste removal, which supports organoid growth and maturation. Recent studies demonstrate that vascularized organoid models offer insights into tissue interactions and promote tissue regeneration. However, the current limitations in establishing functional vascular networks affect organoid growth, viability, and clinical translation potential. This review examines the development of vascularized organoids, including the mechanisms of angiogenesis and vasculogenesis, construction strategies, and biomedical applications. The approaches are categorized into in vivo and in vitro methods, with analysis of their specific advantages and limitations. The review also discusses emerging techniques such as bioprinting and gene editing for improving vascularization and functional integration in organoid-based therapies. Current developments in organoid vascularization indicate potential applications in modeling human diseases and developing therapeutic strategies, contributing to advances in translational research.

Proximal Femoral Focal Deficiency (PFFD) is the most proximal manifestation of a syndrome involving Congenitally Shortened lower Limbs (CSL), which also affects the fibula and midline metatarsals. This pattern of congenital human long bone deficiencies corresponds, in a time dependent manner, to the failed ingrowth pathways of new blood vessels of the growing embryonic limb. The distal femoral condyles are, in contrast, served by an alternative vascular supply from around the knee joint, and so remain resistant to the CSL deficiency.

We hypothesize that embryonic vascular dysgenesis causes PFFD, as well as the cardinal features of the Femoral, Fibular and midline Metatarsal deficiencies (FFM) syndrome.

Arteriography of CSL with PFFD reveals diminution or failed formation of the Femoral Artery (FA), which corresponds to downstream skeletal reductions. It may also reveal preservation of the primitive Axial Artery (AA) of the embryonic limb. The combination of missing and retained primitive vessels inform the time, place, and nature of the etiologic vascular events. This suggests that PFFD is the visible expression of a normally prefigured cartilaginous scaffold of the femur, which develops in conformity with the available pattern of blood vessels present. The teratogen thalidomide, known to affect the forming embryonic vasculature, also produces PFFD indistinguishable from the naturally occurring entity.

The entire spectrum of PFFD, including phocomelia, fibular, and metatarsal dystrophisms, should thus be regarded as downstream skeletal results of embryonic arterial dysgeneses.

During angiogenesis, endothelial cells expand the vasculature by migrating from existing blood vessels, proliferating and collectively organizing into new capillaries. In vitro and in vivo experimentation is instrumental for identifying the molecular players and cell behaviour that regulate angiogenesis. Alongside experimental work, computational and mathematical models of endothelial cell network formation have helped to analyse if the current molecular and cellular understanding of endothelial cell behaviour is sufficient to explain the formation of endothelial cell networks. As input, the models take (a subset of) the current knowledge or hypotheses of single cell behaviour and capture it into a dynamical, mathematical description. As output, they predict the multicellular behaviour following from the actions of many individual cells, i.e., formation of a vascular-like network. Paradoxically, computational modelling based on different assumptions, i.e., completely different, sometimes non-intersecting sets of observed single cell behaviour, can reproduce the same angiogenesis-like multicellular behaviour, making it practically impossible to decide which, if any, of these models is correct. Here we present dynamical analyses of time-lapses of in vitro endothelial cell network formation experiments and compare these with dynamic analyses of three mathematical models: (1) the cell elongation model; (2) the contact-inhibited chemotaxis model; and (3) the mechanical cell-cell communication model. We extract a variety of dynamical characteristics of endothelial cell network formation using a custom time-lapse video analysis pipeline in ImageJ. We compare the dynamical network characteristics of the in vitro experiments to those of the cellular networks produced by the computational models. We test the response of the in silico dynamical cell network characteristics to changes in cell density and make related changes in the in vitro experiments. Of the three computational models that we have considered, the cell elongation model best captures the remodelling phase of in vitro endothelial cell network formation. Furthermore, in the in vitro model, the final size and number of lacunae in the network are independent of the initial cell density. This observation is also reproduced in the cell elongation model, but not in the other two models that we have considered. Altogether, we present an approach to model validation based on comparisons of time-resolved data and variations of model conditions.

One of the long-standing challenges in the field of tissue repair and regeneration is the rapid establishment of local microvascular circulation and restoration of perfusion at the site of defects or injuries. Recently, adipose tissue-derived microvascular fragments (ad-MVFs) have attracted increasing attention from researchers. Adipose tissue is rich in blood vessels, and significant progress has been made in the extraction and preservation techniques for microvascular fragments within it. Ad-MVFs promote tissue and organ repair and regeneration through three main mechanisms. First, they accelerate rapid and efficient vascularization at the injury site, enabling early vessel perfusion. Second, the stem cell components within ad-MVFs provide a rich source of cells for tissue and organ regeneration. Third, they play a role in immune regulation, facilitating integration with host tissues after implantation. The application methods of ad-MVFs are diverse. They can be directly implanted or pre-cultivated, facilitating their combination with various scaffolds and broadening their application scope. These properties have led to the wide use of ad-MVFs in tissue engineering, with promising prospects. This review demonstrates that ad-MVFs can serve as a reliable and highly feasible unit for tissue regeneration.

Chronic nonhealing ulcers are responsible for considerable morbidity, given the increasing prevalence of type II diabetes and other comorbid conditions that further worsen healing. This study introduced shelf-stable decellularized and lyopreserved human amnion grafts for treating difficult-to-heal wounds. The processing approach (comprising a unique combination of nonionic surfactants and trehalose lyopreservation) applied to develop these bioscaffolds maximized the retention of sulfated glycosaminoglycans while enhancing both tensile property and hydrophilicity. Postprocessing, the tensile properties were found to be similar to human skin (5.33 ± 2.45 MPa). Additionally, the surface hydrophilicity of the lyopreserved grafts was increased. It also exhibited optimum moisture transmissibility (evaluated as per BS EN 13726-2 standards), similar to moist wound dressing (1625 ± 375 g/m2/day). Biochemical attributes including total acid-soluble proteins (481.140 ± 14.95 μg/mL) and collagen (9.01 ± 0.15 mg/mL) were well retained as compared to the fresh membrane. Notably, the sulfated glycosaminoglycan content of the processed grafts was well conserved (there was only a 21.14% reduction, which was substantially lower than the reduction achieved by conventionally used surfactants for processing biological tissues). The regenerative efficacy of these bioactive scaffolds was evaluated through preclinical testing in a diabetic rodent wound model. It showed a 50% reduction in time to heal compared to the standard of care dressings, supported by increased vascular endothelial growth factor (VEGF) expression in the healed tissues. This can be collectively attributed to the conservation of sulfated glycosaminoglycans (GAGs) and the enhanced scaffold tensile quality, which play key roles in promoting angiogenesis, and tissue regeneration in diabetic wound beds. As a result, these grafts are well suited for a variety of soft tissue reconstruction applications and can also serve as bioactive scaffolds for culturing autologous cells, making them versatile tools in regenerative medicine.

Some cancer patients derive limited benefit from anti-angiogenic therapy or discontinuation due to adverse reactions. Vascular endothelial growth factor receptor 2 (VEGFR2) plays an important role in regulating angiogenesis in tumors. This study aims to evaluate the association of VEGFR2 polymorphisms with clinical outcomes of anti-angiogenic drugs (AADs) in cancer patients.

PubMed, Embase, Web of Science, and the Cochrane Library were searched from inception to Dec 26, 2023. Studies accessing the association of VEGFR2 polymorphisms with efficacy and/or safety of AADs in patients with solid tumor were included.

A total of 32 studies encompassing 7075 patients were identified. The T allele of rs2305948 (C > T) was significantly associated with worse progression-free survival and overall survival, especially in Asians, patients with the dominant model (CT/TT vs. CC), bevacizumab-treated patients, colorectal cancer patients, and non-small cell lung cancer patients. The C allele of rs2071559 (T > C) was markedly associated with worse PFS and OS, specifically in the dominant model (CC/CT vs. TT), apatinib-treated patients, and non-small cell lung cancer patients. The A allele of rs1870377 (T > A) was significantly associated with improved PFS, particularly in patients with renal cell carcinoma. However, this A allele also significantly increased the risk of hypertension. No significant associations were observed for rs2305948 (G > A), rs11133360 (T > C), and rs12505758 (T > C) with the clinical outcomes of AADs.

Among VEGFR2 polymorphisms, rs2305948 (C > T) and rs2071559 (T > C) were associated with a high risk of disease progression and death, rs1870377 (T > A) was associated with improved PFS but an increased risk of hypertension.

Diabetes is a chronic disease that affects many people, with both its incidence and prevalence rising globally. Diabetes can lead to various complications, among which cognitive impairment in diabetic patients significantly impacts their daily life and blood glucose management, complicating treatment and worsening prognosis. Therefore, the early diagnosis and treatment of cognitive impairment are essential to ensure the health of diabetic patients. However, there is currently no widely accepted and effective method for the early diagnosis of diabetes-related cognitive impairment. This review aims to summarize potential screening and diagnostic methods, as well as biomarkers, for cognitive impairment in diabetes, including retinal structure and function examination, brain imaging, and peripheral blood biomarkers, providing valuable information and support for clinical decision making and future research.

The prognosis of ground glass opacity featured lung adenocarcinomas (GGO-LUAD) is significantly better than that of solid nodule featured lung adenocarcinomas (SN-LUAD), but the specific reasons behind their indolent tumor behavior are still unclear. The purpose of this study is to investigate their differences in intratumoral microvessels, related angiogenic factors and important stromal cells.

Thirty patients (15 paired patients only with GGO or SN) diagnosed with pathological stage 0-I lung adenocarcinoma who underwent surgical treatment were included into this study. Immunohistochemistry was performed to stain the blood vessel markers (CD31, CD34 and CD105), LYVE-1, the cancer-associated fibroblasts (CAFs) markers (α-SMA and S100A4), TGF-β and HIF-1α from 30 patients tissue sections. At the same time, Ki67 Labeling Index (LI) extracted from pathological report of all patients was also analyzed.

GGO-LUAD is more abundant than SN-LUAD in lymphatic vessel density (LVD), but similar in total microvessel density (CD31 + MVD). However, GGO-LUAD is significantly lower than SN-LUAD in CD34 + MVD and CD105 + MVD. In terms of TGF-β, HIF-1α expression and Ki67 LI level, GGO-LUAD was also significantly weaker than SN-LUAD. Moreover, the distribution of CAFs in GGO-LUAD is less than that in SN-LUAD. Regardless of the pathological type (adenocarcinoma in situ (AIS) or minimally invasive adenocarcinoma (MIA) or invasive lung adenocarcinoma (IAC)), there is no difference in any of the above indicators in GGO-LUAD.

Our finding displays that GGO-LUAD was significantly lower than SN-LUAD in CD34 + MVD and CD105 + MVD reflecting tumor angiogenesis, and the distribution of CAFs and factors related to tumor angiogenesis were also significantly lower in GGO-LUAD, which may indicate that the weak ability of angiogenesis might be the reason for the good prognosis of GGO-LUAD.

The most common types of renal carcinoma is kidney renal clear cell carcinoma (KIRC). ESM1 is a secreted protein, which involved in, lipids and glucose metabolism, but their role in angiogenesis is contradictory in different disease, especially in KIRC. Bioinformatic analysis confirmed the ESM1 expression and prognosis in KIRC. IHC staining revealed protein expression of ESM1 in KIRC samples. The role of ESM1 in KIRC proliferation and migration were tested by MTT, EdU, transwell analysis. The role of its paracrine function in KIRC angiogenesis was tested by functional experiments. The downstream molecular mechanism of ESM1 were further elucidated by WB and functional experiments. ESM1 was significantly increased in KIRC with prognostic significance. ESM1 knockdown inhibited the invasiveness capability and viability of KIRC cell. The paracrine of ESM1 enhanced HUVECs proliferation and migration to format tube in KIRC cell conditional medium. ESM1 knockdown induced the inactivation of Akt/mTOR and Ras pathway to attenuate proliferation, migration, invasion and angiogenesis in KIRC. ESM1 was a key role in the tumor microenvironment (TME) of KIRC, which promoted the proliferation, migration, invasion, and angiogenesis by activating Akt/mTOR and Ras pathway. It is a potential therapeutic target for KIRC patients.

Venous aneurysms of the lower limbs are rare, and those located in the popliteal area are the most described. Congenital anatomical variations have been reported but are also exceptional. They can affect both superficial and deep veins. The risk of thromboembolism is present in deep locations, particularly in the popliteal area or in venous drainage malformations. We report the case of a pulmonary embolism revealing a venous aneurysm involving an atypical drainage vein. The contribution of Doppler ultrasound, CT scan, MRI, and venous Doppler was crucial for establishing the diagnosis. Surgery is the treatment of choice, combining in our case aneurysmorrhaphy and anticoagulation, with good patency observed in follow-up controls.

There is a current lack of consensus on whether the ancestral parity mode was oviparity (egg-laying) or viviparity (live-birth) in amniotes and particularly in squamates (snakes, lizards, and amphisbaenids). How transitions between parity modes occur at the genomic level has primary importance for how science conceptualises the origin of amniotes, and highly variable parity modes in Squamata. Synthesising literature from medicine, poultry science, reproductive biology, and evolutionary biology, I review the genomics and physiology of five broad processes (here termed the 'Main Five') expected to change during transitions between parity modes: eggshell formation, embryonic retention, placentation, calcium transport, and maternal-fetal immune dynamics. Throughout, I offer alternative perspectives and testable hypotheses regarding proximate causes of parity mode evolution in amniotes and squamates. If viviparity did evolve early in the history of lepidosaurs, I offer the nucleation site hypothesis as a proximate explanation. The framework of this hypothesis can be extended to amniotes to infer their ancestral state. I also provide a mechanism and hypothesis on how squamates may transition from viviparity to oviparity and make predictions about the directionality of transitions in three species. After considering evidence for differing perspectives on amniote origins, I offer a framework that unifies (i) the extended embryonic retention model and (ii) the traditional model which describes the amniote egg as an adaptation to the terrestrial environment. Additionally, this review contextualises the origin of amniotes and parity mode evolution within Medawar's paradigm. Medawar posited that pregnancy could be supported by immunosuppression, inertness, evasion, or immunological barriers. I demonstrate that this does not support gestation or gravidity across most amniotes but may be an adequate paradigm to explain how the first amniote tolerated internal fertilization and delayed egg deposition. In this context, the eggshell can be thought of as an immunological barrier. If serving as a barrier underpins the origin of the amniote eggshell, there should be evidence that oviparous gravidity can be met with a lack of immunological responses in utero. Rare examples of two species that differentially express very few genes during gravidity, suggestive of an absent immunological reaction to oviparous gravidity, are two skinks Lampropholis guichenoti and Lerista bougainvillii. These species may serve as good models for the original amniote egg. Overall, this review grounds itself in the historical literature while offering a modern perspective on the origin of amniotes. I encourage the scientific community to utilise this review as a resource in evolutionary and comparative genomics studies, embrace the complexity of the system, and thoughtfully consider the frameworks proposed.

ObjectiveStem cell therapy can modify angiogenic pathways. Neural protein 3.1 (P311) possesses the pro-angiogenic property. This study strived to explore the action and mechanism of human adipose mesenchymal stem cells (hADSCs) in human brain microvascular endothelial cell (hBMEC) injury by regulating P311.MethodsThe hADSCs of the 3rd passage were stained with oil red O, Alizarin red, and Alcian blue to assess adipogenic, osteogenic, and chondrogenic differentiation, followed by an analysis of immune phenotype via flow cytometry. After culturing hADSCs in hypoxic (5% oxygen) and normoxic (20% oxygen) conditions, extracellular vesicles (EVs) were extracted via ultracentrifugation, followed by morphology observation by microscopy, size distribution analysis via Nanoparticle tracking analysis, and surface marker determination by Western blot. hBMECs were treated with lipopolysaccharide (LPS) and cultured with normoxia or hypoxic hADSC-EVs. The effects of normoxia and hypoxic hADSC-EVs on proliferation, migration, and tube formation of hBMECs were assessed via CCK-8, Transwell, and tube formation assays. hBMECs were transfected with pcDNA3.0-P311 or P311 siRNA to evaluate the action of P311 on hBMEC injury.ResultsHypoxic hADSC-EVs had a larger mean diameter, a wider diameter distribution range, and a higher particle concentration than normoxic hADSC-EVs. Hypoxia and normoxic hADSC-EVs were internalized by hBMECs, and hypoxic hADSC-EVs were more internalized. LPS suppressed hBMEC proliferation, migration, and tube formation and induced hBMEC injury. Hypoxia and normoxic hADSC-EVs ameliorated hBMEC injury, and hypoxic hADSC-EVs were superior to normoxic hADSC-EVs. P311 overexpression mitigated hBMEC injury, whereas P311 knockdown partly averted hypoxic hADSC-EV-exerted suppression on hBMEC injury.ConclusionHypoxic hADSC-EVs can protect against LPS-induced hBMEC injury by upregulating P311.

The central nervous system (CNS) requires specialized blood vessels to support neural function within specific microenvironments. During neurovascular development, endothelial Wnt/β-catenin signaling is required for BBB development within the brain parenchyma, whereas fenestrated blood vessels that lack BBB properties do not require Wnt/β-catenin signaling. Here, we used zebrafish to further characterize this phenotypic heterogeneity of the CNS vasculature. Using transgenic reporters of Wnt/β-catenin transcriptional activity, we found an inverse correlation between activated Wnt/β-catenin signaling in endothelial cells (ECs) versus non-ECs within these distinct microenvironments. Our results indicated that the level of Wnt/β-catenin signaling in non-ECs may regulate Wnt/β-catenin activity in adjacent ECs. To further test this concept, we generated a transgenic Tet-On inducible system to drive constitutively active β-catenin expression in neural progenitor cells (NPCs). We found that dose-dependent activation of Wnt/β-catenin in NPCs caused severe deficiency in CNS angiogenesis and BBB development. Additionally, we discovered a significant increase in the proliferation of microglia and infiltration of peripheral neutrophils indicative of a stereotypical neuroinflammatory response. In conclusion, our results demonstrate the importance of proper Wnt/β-catenin signaling within specific CNS microenvironments and highlights the potentially deleterious consequences of aberrant Wnt activation.

Due to its intricate molecular and structural characteristics, vascular endothelial growth factor receptor 2 (VEGFR-2) is essential for the development of new blood vessels in various pathological processes and conditions, especially in cancers. VEGFR-2 inhibitors have demonstrated significant anticancer effects by blocking many signaling pathways linked to tumor growth, metastasis, and angiogenesis. Several small compounds, including the well-tolerated sunitinib and sorafenib, have been approved as VEGFR-2 inhibitors. However, the widespread side effects linked to these VEGFR-2 inhibitors-hypertension, epistaxis, proteinuria, and upper respiratory infection-motivate researchers to search for new VEGFR-2 inhibitors with better pharmacokinetic profiles. The key molecular interactions required for the interaction of the small molecules with the protein target to produce the desired pharmacological effects are identified using computer-aided drug design (CADD) methods such as pharmacophore and QSAR modeling, structure-based virtual screening, molecular docking, molecular dynamics (MD) simulation coupled with MM/PB(GB)SA, and other computational strategies. This review discusses the applications of these methods for VEGFR-2 inhibitor design. Future VEGFR-2 inhibitor designs may be influenced by this review, which focuses on the current trends of using multiple screening layers to design better inhibitors.

The blood-brain barrier (BBB) is a highly dynamic and complex structure, present throughout the brain vasculature, that safeguards the brain against blood-borne insults. Neuroglial cells play a major role in its development, function, and homeostasis of the BBB by establishing intricate interactions via direct cell-cell contacts and paracrine signaling. Astrocytes, pericytes, oligodendrocytes, and microglia, alongside specialized brain endothelial cells, orchestrate key events in the brain in health and disease, which can be partially recapitulated by in vitro and in vivo models for biomedical research. This chapter presents a detailed description of the main cellular and molecular mechanisms that govern the neuroglia-BBB crosstalk and the available models for its investigation, emphasizing the importance of each cell population and the synergistic roles they play in the brain.

Extracranial arteriovenous malformations (eAVMs) are complex vascular lesions characterized by anomalous arteriovenous connections, vascular instability, and disruptions in endothelial cell (EC)-to-mural cell (MC) interactions. This study sought to determine whether eAVM-MCs could induce endothelial-to-mesenchymal transition (EndMT), a process known to disrupt vascular integrity, in the eAVM microenvironment. eAVM and paired control tissues were analyzed using RT-PCR for EC (CD31, CD34, and CDH5) and EndMT-specific markers (SNAI1, SNAI2, ACTA2/α-SMA, N-cadherin/CDH2, VIM). Immunohistochemistry (IHC) was also performed to analyze MC- (PDGFR-β and α-SMA), EC (CD31, CD34, and CDH5), and EndMT-specific markers (CDH2 and SNAI1) in sequential paraffin-embedded sections of eAVM patient biopsies and in adjacent normal tissue biopsies from the same patients. Furthermore, eAVM-MCs and MCs from normal paired tissues (NMCs) were then isolated from fresh human surgical samples using flow cytometry and co-cultured with normal human umbilical vein vascular endothelial cells (HUVECs), followed by analysis of CD31 by immunofluorescence. RT-PCR analysis did not show a significant difference in the expression of EC markers between eAVM tissues and controls, whereas expression of EndMT-specific markers was upregulated in eAVM tissues compared to controls. IHC of eAVMs and paired control tissues demonstrated regions of significant perivascular eAVM-MC expansion (PDGFR-β+, and α-SMA+) surrounding dilated, morphologically abnormal vessels. These regions contained endothelium undergoing EndMT as evidenced by loss of CD31, CD34, and CDH5 expression and upregulation of the EndMT-associated genes CDH2 and SNAI1. Isolated eAVM-MCs induced loss of CD31 in HUVECs when grown in co-culture, while NMCs did not. This study suggests that the eAVM endothelium surrounded by expanded eAVM-MCs undergoes EndMT, potentially leading to the formation of dilated and fragile vessels, and implicates the eAVM-MCs in EndMT initiation and eAVM pathology.

Peptide Lv is a small endogenous secretory peptide with ~40 amino acids and is highly conserved among certain several species. While it was first discovered that it augments L-type voltage-gated calcium channels (LTCCs) in neurons, thus it was named peptide "Lv", it can bind to vascular endothelial growth factor receptor 2 (VEGFR2) and has VEGF-like activities, including eliciting vasodilation and promoting angiogenesis. Not only does peptide Lv augment LTCCs in neurons and cardiomyocytes, but it also promotes the expression of intermediate-conductance KCa channels (KCa3.1) in vascular endothelial cells. Peptide Lv is upregulated in the retinas of patients with early proliferative diabetic retinopathy, a disease involving pathological angiogenesis. This review will provide an overview of peptide Lv, its known bioactivities in vitro and in vivo, and its clinical relevance, with a focus on its role in angiogenesis. As there is more about peptide Lv to be explored, this article serves as a foundation for possible future developments of peptide Lv-related therapeutics to treat or prevent diseases.

Accumulation of senescent endothelial cells (ECs) in vasculature represents a key step in the development of vascular aging and ensuing age-related diseases. Given that removal of senescent ECs may prevent disease and improve health and wellbeing, the discovery of novel biomarkers that effectively identify senescent cells is of particular importance. As crucial elements for biological pathways and reliable bioindicators of cellular processes, metabolites demand attention in this context. Using senescent human brain microvascular endothelial cells (HBMECs) displaying a secretory phenotype and significant morphological, nuclear, and enzymatic changes compared to their young counterparts, this study has shown that senescent HBMECs lose their endothelial characteristics as evidenced by the disappearance of CD31/PECAM-1 from interendothelial cell junctions. The metabolic profiling of young versus senescent HBMECs also indicates significant differences in glucose, glutamine, and fatty acid metabolism. The analysis of intracellular and secreted metabolites proposes L-proline, L-glutamate, NAD+, and taurine/hypotaurine pathway components as potential biomarkers. However, further studies are required to assess the value of these agents as potential biomarkers and therapeutic targets.

Transmembrane-4 L-six family member-1 (TM4SF1) is a small cell surface glycoprotein that is highly and selectively expressed on endothelial cell and mesenchymal stem cell surfaces. TM4SF1 regulates cellular functions by forming protein complexes called TMED (TM4SF1-enriched microdomains) that either recruit growth-factor activated proteins and internalize them via microtubules to distribute the recruited molecules intracellularly or support the formation of nanopodia for intercellular interactions extracellularly. Through a genetically manipulated mouse model for global Tm4sf1 gene knockout, we demonstrate here that TM4SF1 is essential for blood vessel development. Tm4sf1-null embryos fail to develop blood vessels and experience lethality at E9.5. Tm4SF1-heterozygous embryos are smaller in body size during early embryonic development, and almost half die in utero due to intracranial hemorrhage in the intraventricular and subarachnoid space, which becomes apparent by E17.5. Surviving Tm4SF1-heterozygotes do not display overt phenotypic differences relative to wild type littermates postnatally. Together, these studies demonstrate that TM4SF1, through its molecular facilitator and nanopodia formation roles in TMED, intimately regulates blood vessel formation during embryonic development.

Cancer remains one of the leading causes of death worldwide and poses a significant challenge to effective treatment due to its complexity. Angiogenesis, the formation of new blood vessels, is one of the cancer hallmarks and is a critical process in tumor growth and metastasis. The pivotal role of angiogenesis in cancer development has made antiangiogenic treatment a promising strategy for cancer therapy. To develop an effective therapy, it is essential to understand the basics of the physiological and tumor angiogenesis process. This review presents the primary factors related to physiological and tumor angiogenesis and the mechanisms of angiogenesis in tumors. We summarize potential molecular targets for cancer treatment by focusing on the vasculature, with the VEGF/VEGFR pathway being one of the most important and well-studied. Additionally, we present the advantages and limitations of currently used clinical protocols for cancer treatment targeting the VEGF/VEGFR pathway.

Fine-tuning angiogenesis, the development of new blood vessels, is essential for maintaining a healthy circulatory and lymphatic system. The small glycoprotein vascular endothelial growth factors (VEGF) are the key mediators in this process, binding to their corresponding membrane-bound VEGF receptors (VEGFRs) to activate angiogenesis signaling pathways. These pathways are crucial throughout human life as they are involved in lymphatic and vascular endothelial cell permeability, migration, proliferation, and survival. Neovascularization, the formation of abnormal blood vessels, occurs when there is a dysregulation of angiogenesis and can result in debilitating disease. Hence, VEGFRs have been widely studied to understand their role in disease-causing angiogenesis. VEGFR1, also known as Fms-like tyrosine kinase-1 (FLT-1), is also found in a soluble form, soluble FLT-1 or sFLT-1, which is known to act as a VEGF neutralizer. It is incorporated into anti-VEGF therapy, designed to treat diseases caused by neovascularization. Here we review the journey of sFLT-1 discovery and delve into the alternative splicing mechanism that creates the soluble receptor, its prevalence in disease states, and its use in current and future potential therapies.

A major roadblock in implementing engineered tissues clinically lies in their limited vascularization. After implantation, such tissues do not integrate with the host's circulation as quickly as needed, commonly resulting in loss of viability and functionality. This study presents a solution to the vascularization problem that could enable the survival and function of large, transplantable, and vascularized engineered tissues. The technique allows vascularization of a cell laden hydrogel through angiogenesis from a suturable tissue-engineered vascular graft (TEVG) constructed from electrospun polycaprolactone with macropores. The graft is surrounded by a layer of cell-laden gelatin-methacryloyl hydrogel. The constructs are suturable and possess mechanical properties like native vessels. Angiogenesis occurs through the pores in the graft, resulting in a hydrogel containing an extensive vascular network that is connected to an implantable TEVG. The size of the engineered tissue and the degree of vascularization can be increased by adding multiple TEVGs into a single construct. The engineered tissue has the potential to be immediately perfused by the patient's blood upon surgical anastomosis to host vessels, enabling survival of implanted cells. These findings provide a meaningful step to address the longstanding problem of fabricating suturable pre-vascularized tissues which could survive upon implantation in vivo. STATEMENT OF SIGNIFICANCE: Creating vascularized engineered tissues that can be transplanted and rapidly perfused by the host blood supply is a major challenge which has limited the clinical impact of tissue engineering. In this study we demonstrate a technique to fabricate vascularized tissue constructs via angiogenesis from a suturable tissue-engineered vascular graft. The macroporous graft is surrounded with hydrogel, allowing endothelial cells to migrate from the lumen and vascularize the hydrogel layer with capillary-like structures connected to the macrovessel. The graft has comparable mechanical properties to native blood vessels and larger constructs can be fabricated by incorporating multiple grafts. These constructs could potentially be connected surgically to the circulation at an implantation site to support their immediate perfusion and survival.

To compare the differences in risk factors and etiological classification between cerebral infarction in young patients and elderly patients, and explore the correlation between cerebral infarction in young patients and white matter lesions (WMLs).

Sixty young patients with cerebral infarction and 142 elderly patients with cerebral infarction were included. The distributions of risk factors such as hypertension, diabetes, heart disease, smoking status, alcohol consumption status, migraine status, and WMLs in the two groups were carefully investigated and statistically analyzed.

According to the univariate analysis, the proportions of males, obese patients, patients with migraine, and patients with obstructive sleep apnea-hypopnea syndrome (OSAHS) in the young group were significantly greater than those in the elderly group. Hypertension, heart disease, and hyperhomocysteinemia were significantly more common in the elderly group than in the young group. According to the TOAST classification, the incidence of stroke of undetermined etiology in the young group was greater than that in the elderly group, whereas the incidence of large-artery atherosclerosis (LAA) in the elderly group was greater than that in the young group. Binary logistic regression analysis revealed that male sex, migraine status, and obstructive sleep apnea-hypopnea syndrome were independently associated with cerebral infarction in young adults, whereas hypertension, heart disease, and hyperhomocysteinemia were independently related to cerebral infarction in elderly individuals. In addition, the incidence of WMLs in the migraine group of young cerebral infarction patients was significantly greater than that in the nonmigraine group.

Compared with those in elderly patients with cerebral infarction, the risk factors for cerebral infarction in young patients are relatively controllable. Furthermore, more methods are needed to determine the etiology of unexplained cerebral infarction in young patients. WMLs are thought to have a relatively high incidence in young patients with cerebral infarction and are significantly associated with migraine.

Endothelial cells are key players in the cardiovascular system. Among other things, they are responsible for sprouting angiogenesis, the process of new blood vessel formation essential for both health and disease. Endothelial cells are strongly regulated by the juxtacrine signaling pathway Notch. Recent studies have shown that both Notch and angiogenesis are influenced by extracellular matrix stiffness; however, the underlying mechanisms are poorly understood. Here, we addressed this challenge by combining computational models of Notch signaling and YAP/TAZ, stiffness- and cytoskeleton-regulated mechanotransducers whose activity inhibits both Dll4 (Notch ligand) and LFng (Notch-Dll4 binding modulator). Our simulations successfully mimicked previous experiments, indicating that this YAP/TAZ-Notch crosstalk elucidates the Notch and angiogenesis mechanoresponse to stiffness. Additional simulations also identified possible strategies to control Notch activity and sprouting angiogenesis via cytoskeletal manipulations or spatial patterns of alternating stiffnesses. Our study thus inspires new experimental avenues and provides a promising modeling framework for further investigations into the role of Notch, YAP/TAZ, and mechanics in determining endothelial cell behavior during angiogenesis and similar processes.

Fucoxanthin, a dietary carotenoid, is predominantly found in edible brown algae and is commonly consumed worldwide. Fucoxanthin has been shown to possess beneficial health activities such as antidiabetic, anti-inflammatory, antimutagenic, and antiobesity; however, the effects of fucoxanthin on VEGF-mediated angiogenesis and its possible binding with VEGF are unknown. Here, different lines of evidence supported the suppressive roles of fucoxanthin in VEGF-mediated angiogenesis. In human umbilical vein endothelial cells, fucoxanthin remarkedly suppressed VEGF-mediated cell proliferative, migration, and invasive abilities, as well as tube formation, without cytotoxicity. In addition, fucoxanthin inhibited the subintestinal vessel formation of zebrafish in vivo. In signaling cascades, fucoxanthin was proposed to interact with VEGF, thus attenuating VEGF's functions in activating the VEGF receptor and its related downstream signaling, i.e., phosphorylations of MEK and Erk. Fucoxanthin also significantly blocked VEGF-triggered ROS formation. Furthermore, the outcomes of applying fucoxanthin in cancer cells were identified, which included (i) inhibiting VEGF-mediated cell proliferation and migration and (ii) inhibiting NF-κB translocation via limiting MMP2 expression. These lines of investigations supported the antiangiogenic roles of fucoxanthin, as well as reviewing its signaling mechanisms, in blocking the VEGF-triggered responses. The results would benefit the potential development of fucoxanthin for the prevention and treatment of angiogenesis-related diseases.

Prostate Cancer (PCa) is an abnormal cell growth within the prostate. This condition is the second most widespread malignancy in elderly males and one of the most frequently diagnosed life-threatening conditions. The Androgen receptor signaling pathway played a crucial role in the initiation and spread to increase the risk of PCa. Hence, targeting the AR receptor signaling pathway is a key strategy for a therapeutic plan for PCa. Our study focuses on recognizing potential inhibitors for dual targeting in PCa by using the in-silico approach. In this study, we target the two enzymes that are CYP17A1 (3RUK) and 5α-reductase (3G1R) responsible for PCa, with the help of phytoconstituents. The natural plant contains various phytochemical types produced from secondary metabolites and used as a medical treatment. The in-silico investigation of phytoconstituents and enzymes was done by approaching molecular docking, ADMET analysis, and high-level molecular dynamic simulation used to assess the stability and binding affinities of the protein-ligand complex. Some phytoconstituents, such as Peonidin, Pelargonidin, Malvidin and Berberine show complex has good molecular interaction with protein. The reliability of the docking scores was examined using a molecular dynamic simulation, which revealed that the complex remained stable throughout the simulation, which ranged from 0 to 200 ns. The selected hits may be effective against CYP17A1 (3RUK) and 5α-reductase (3G1R) (PCa) using a computer-aided drug design (CADD) method, which further enables researchers for upcoming in-vivo and in-vitro research, according to our in-silico approach.Communicated by Ramaswamy H. Sarma.

After September 11, 2001, nuclear threat prompted government agencies to develop medical countermeasures to mitigate two syndromes, the hematopoietic-acute radiation syndrome (H-ARS) and the higher-dose gastrointestinal-acute radiation syndrome (GI-ARS), both lethal within weeks. While repurposing leukemia drugs that enhance bone marrow repopulation successfully treats H-ARS, no mitigator potentially deliverable under mass casualty conditions preserves the GI tract. We recently reported that anti-ceramide single-chain variable fragment (scFv) mitigates GI-ARS lethality, abrogating ongoing small intestinal endothelial apoptosis to rescue Lgr5+ stem cells. Here, we examine long-term consequences of prevention of acute GI-ARS lethality.

For these studies, C57BL/6J male mice were treated with 15 Gy whole body irradiation, the 90% GI-ARS lethal dose for this mouse strain.

Mice irradiated with 15 Gy alone or with 15 Gy + bone marrow transplantation (BMT) or anti-ceramide scFv, succumb to an ARS within 8 to 10 days. Autopsies reveal only mice receiving anti-ceramide scFv at 24 hours post-whole body irradiation display small intestinal rescue. No marrow reconstitution occurs in any group with attendant undetectable circulating blood elements. Mice receiving 15 Gy + BMT + scFv, however, normalize blood counts by day 12, suggesting that scFv also improves marrow reconstitution, a concept for which we provide experimental support. We show that at 14 Gy, the upper limit dose for H-ARS lethality before transition to GI-ARS lethality, anti-ceramide scFv markedly improves marrow take, reducing the quantity of marrow-conferring survival by more than 3-fold. Consistent with these findings, mice receiving 15 Gy + BMT + scFv exhibit prolonged survival. At day 90, before sacrifice, they display normal appearance, behavior, and serum biochemistries, and surprisingly, at full autopsy, near-normal physiology in all 42 tissues examined.

Anti-ceramide scFv mitigates GI-ARS lethality and improves marrow reconstitution rendering prolonged survival with near normal autopsies.

Melanoma is the deadliest form of skin cancer in the United States, with its incidence rates rising in older populations. As the immune system undergoes age-related changes, these alterations can significantly influence tumor progression and the effectiveness of cancer treatments. Recent advancements in understanding immune checkpoint molecules have paved the way for the development of innovative immunotherapies targeting solid tumors. However, the aging tumor microenvironment can play a crucial role in modulating the response to these immunotherapeutic approaches. This review seeks to examine the intricate relationship between age-related changes in the immune system and their impact on the efficacy of immunotherapies, particularly in the context of melanoma. By exploring this complex interplay, we hope to elucidate potential strategies to optimize treatment outcomes for older patients with melanoma, and draw parallels to other cancers.

Scientists have been exploring anti-angiogenic strategies to inhibit angiogenesis and prevent tumor growth. Vasculogenic mimicry (VM) in glioblastoma multiforme (GBM) poses a challenge, complicating anti-angiogenesis therapy. A novel drug, GN25 (3-[{1,4-dihydro-5,8-dimethoxy-1,4-dioxo-2-naphthalenyl}thio]-propanoic acid), can inhibit tumor formation. This study aims to investigate the microenvironmental effects and molecular mechanisms of GN25 in anti-angiogenesis and anti-VM.

MTT (3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide) assay was used to evaluate the cell viability of different concentrations of GN25 in human umbilical vein endothelial cells (HUVEC) and Uppsala 87 malignant glioma (U87MG) cells. Functional assays were used to investigate the effects of GN25 on angiogenesis-related processes, whereas gelatin zymography, enzyme-linked immunosorbent assays, and Western blotting were utilized to assess the influence on matrix metalloproteinase (MMP)-2 and vascular endothelial growth factor (VEGF) secretion and related signaling pathways.

GN25 suppressed migration, wound healing, and tube formation in HUVECs and disrupted angiogenesis in a rat aorta ring and zebrafish embryo model. GN25 dose-dependently reduced phosphatidylinositol 3-kinase/AKT and inhibited MMP-2/VEGF secretion in HUVECs. In U87MG cells, GN25 inhibited migration, wound healing, and VM, accompanied by a decrease in MMP-2 and VEGF secretion. The results indicate that GN25 effectively inhibits angiogenesis and VM formation in HUVECs and U87MG cells without affecting preexisting vascular structures.

This study elaborated GN25's potential as an anti-angiogenic agent by elucidating its inhibitory effects on classical angiogenesis. VM provides valuable insights for developing novel therapeutic strategies against tumor progression and angiogenesis-related diseases. These results indicate the potential of GN25 as a promising candidate for angiogenesis-related diseases.

While the extracellular matrix (ECM) has long been recognized for its structural contributions, anchoring cells for adhesion, providing mechanical support, and maintaining tissue integrity, recent efforts have elucidated its dynamic, reciprocal, and diverse properties on angiogenesis. The ECM modulates angiogenic signaling and mechanical transduction, influences the extent and degree of receptor activation, controls cellular behaviors, and serves as a reservoir for bioactive macromolecules. Collectively, these factors guide the formation, maturation, and stabilization of a functional vascular network. This review aims to shed light on the versatile roles of the ECM in angiogenesis, transcending its traditional functions as a mere structural material. We will explore its engagement and synergy in signaling modulation, interactions with various angiogenic factors, and highlight its importance in both health and disease. By capturing the essence of the ECM's diverse functionalities, we highlight the significance in the broader context of vascular biology, enabling the design of novel biomaterials to engineer vascularized tissues and their potential therapeutic implications.

The vascular network plays an essential role in the maintenance of all organs in the body via the regulated delivery of oxygen and nutrients, as well as tissue communication via the transfer of various biological signaling molecules. It also serves as a route for drug administration and affects pharmacokinetics. Due to this importance, engineers have sought to create physiologically relevant and reproducible vascular systems in tissue, considering cell-cell and extracellular matrix interaction with structural and physical conditions in the microenvironment. Extracellular vesicles (EVs) have recently emerged as important carriers for transferring proteins and genetic material between cells and organs, as well as for drug delivery. Vascularized platforms can be an ideal system for studying interactions between blood vessels and EVs, which are crucial for understanding EV-mediated substance transfer in various biological situations. This review summarizes recent advances in vascularized platforms, standard and microfluidic-based techniques for EV isolation and characterization, and studies of EVs in vascularized platforms. It provides insights into EV-related (patho)physiological regulations and facilitates the development of EV-based therapeutics.

Brain organoids, three-dimensional cell structures derived from pluripotent stem cells, closely mimic key aspects of the human brain in vitro, providing a powerful tool for studying neurodevelopment and disease. The neuroectodermal induction protocol employed for brain organoid generation primarily gives rise to the neural cellular component but lacks the vital vascular system, which is crucial for the brain functions by regulating differentiation, migration, and circuit formation, as well as delivering oxygen and nutrients. Many neurological diseases are caused by dysfunctions of cerebral microcirculation, making vascularization of human brain organoids an important tool for pathogenetic and translational research. Experimentally, the creation of vascularized brain organoids has primarily focused on the fusion of vascular and brain organoids, on organoid transplantation in vivo, and on the use of microfluidic devices to replicate the intricate microenvironment of the human brain in vitro. This review summarizes these efforts and highlights the importance of studying the neurovascular unit in a forward-looking perspective of leveraging their use for understanding and treating neurological disorders.

Vascular endothelial growth factor receptor 2 (VEGFR-2) stands as a prominent therapeutic target in oncology, playing a critical role in angiogenesis, tumor growth, and metastasis. FDA-approved VEGFR-2 inhibitors are associated with diverse side effects. Thus, finding novel and more effective inhibitors is of utmost importance. In this study, a deep learning (DL) classification model was first developed and then employed to select putative active VEGFR-2 inhibitors from an in-house chemical library including 187 druglike compounds. A pool of 18 promising candidates was shortlisted and screened against VEGFR-2 by using molecular docking. Finally, two compounds, RHE-334 and EA-11, were prioritized as promising VEGFR-2 inhibitors by employing PLATO, our target fishing and bioactivity prediction platform. Based on this rationale, we prepared RHE-334 and EA-11 and successfully tested their anti-proliferative potential against MCF-7 human breast cancer cells with IC50 values of 26.78±4.02 and 38.73±3.84 μM, respectively. Their toxicities were instead challenged against the WI-38. Interestingly, expression studies indicated that, in the presence of RHE-334, VEGFR-2 was equal to 0.52±0.03, thus comparable to imatinib equal to 0.63±0.03. In conclusion, this workflow based on theoretical and experimental approaches demonstrates effective in identifying VEGFR-2 inhibitors and can be easily adapted to other medicinal chemistry goals.

Brain arteriovenous malformations (bAVMs) substantially increase the risk for intracerebral hemorrhage (ICH), which is associated with significant morbidity and mortality. However, the treatment options for bAVMs are severely limited, primarily relying on invasive methods that carry their own risks for intraoperative hemorrhage or even death. Currently, there are no pharmaceutical agents shown to treat this condition, primarily due to a poor understanding of bAVM pathophysiology. For the last decade, bAVM research has made significant advances, including the identification of novel genetic mutations and relevant signaling in bAVM development. However, bAVM pathophysiology is still largely unclear. Further investigation is required to understand the detailed cellular and molecular mechanisms involved, which will enable the development of safer and more effective treatment options. Endothelial cells (ECs), the cells that line the vascular lumen, are integral to the pathogenesis of bAVMs. Understanding the fundamental role of ECs in pathological conditions is crucial to unraveling bAVM pathophysiology. This review focuses on the current knowledge of bAVM-relevant signaling pathways and dysfunctions in ECs, particularly the endothelial-to-mesenchymal transition (EndMT).