Store-operated Ca²⁺ entry (SOCE) is activated in response to the inositol-1,4,5-trisphosphate (InsP₃)-dependent depletion of the endoplasmic reticulum (ER) Ca²⁺ store and represents a ubiquitous mode of Ca²⁺ influx. In vascular endothelial cells, SOCE regulates a plethora of functions that maintain cardiovascular homeostasis, such as angiogenesis, vascular tone, vascular permeability, platelet aggregation, and monocyte adhesion. The molecular mechanisms responsible for SOCE activation in vascular endothelial cells have engendered a long-lasting controversy. Traditionally, it has been assumed that the endothelial SOCE is mediated by two distinct ion channel signalplexes, i.e., STIM1/Orai1 and STIM1/Transient Receptor Potential Canonical 1(TRPC1)/TRPC4. However, recent evidence has shown that Orai1 can assemble with TRPC1 and TRPC4 to form a non-selective cation channel with intermediate electrophysiological features. Herein, we aim at bringing order to the distinct mechanisms that mediate endothelial SOCE in the vascular tree from multiple species (e.g., human, mouse, rat, and bovine). We propose that three distinct currents can mediate SOCE in vascular endothelial cells: (1) the Ca²⁺-selective Ca²⁺-release activated Ca²⁺ current (I_CRAC), which is mediated by STIM1 and Orai1; (2) the store-operated non-selective current (I_SOC), which is mediated by STIM1, TRPC1, and TRPC4; and (3) the moderately Ca²⁺-selective, I_CRAC-like current, which is mediated by STIM1, TRPC1, TRPC4, and Orai1.

This review highlights our current knowledge regarding expression of transient receptor potential (TRP) cation channels in lung endothelium and evidence for their involvement in regulation of lung endothelial permeability. Six mammalian TRP families have been identified and organized on the basis of sequence homology: TRPC (canonical), TRPV (vanilloid), TRPM (melastatin), TRPML (mucolipin), TRPP (polycystin), and TRPA (ankyrin). To date, only TRPC1/4, TRPC6, TRPV4, and TRPM2 have been extensively studied in lung endothelium. Calcium influx through each of these channels has been documented to increase lung endothelial permeability, although their channel-gating mechanisms, downstream signaling mechanisms, and impact on endothelial structure and barrier integrity differ. While other members of the TRPC, TRPV, and TRPM families may be expressed in lung endothelium, we have little or no evidence linking these to regulation of lung endothelial permeability. Further, neither the expression nor functional role(s) of any TRPML, TRPP, and TRPA family members has been studied in lung endothelium. In addition to this assessment organized by TRP channel family, we also discuss TRP channels and lung endothelial permeability from the perspective of lung endothelial heterogeneity, using outcomes of studies focused on TRPC1/4 and TRPV4 channels. The diversity within the TRP channel family and the relative paucity of information regarding roles of a number of these channels in lung endothelium make this field ripe for continued investigation.

TRPC-mediated Ca(2+) entry has been implicated in the control of smooth muscle proliferation and might represent a pivotal mechanism underlying in-stent restenosis. As we have observed significant expression of TRPC3 in human smooth muscle from the coronary artery as well as the aorta, we tested the efficiency of a recently discovered TRPC3 selective Ca(2+) entry blocker Pyr3 to prevent vascular smooth muscle proliferation and stent implantation-induced hyperplasia of human aorta. The effect of Pyr3 on proliferation was measured by detection of BrdU incorporation and PCNA expression in human coronary smooth muscle and microvascular endothelium, which displays significantly smaller expression levels of TRPC3 as compared with smooth muscle. Pyr3 inhibited smooth muscle proliferation but lacked detectable effects on endothelial proliferation. Measurements of ATP-induced Ca(2+) signals revealed that Pyr3 suppressed agonist-induced Ca(2+) entry more effectively in vascular smooth muscle than in endothelial cells. Inhibitory effects of Pyr3 on stent implantation-induced arterial injury was tested using a novel in vitro model of in-stent hyperplasia in human arteries based on organ typical culture of human aortic constructs. Pyr3 effectively prevented increases in tissue levels of PCNA and Ki-67 at 2 weeks after stent implantation into human aortae. Similarly, proliferation markers were significantly suppressed when implanting a Pyr3-releasing stent prototype as compared with a bare metal stent (BMS) control. Our results suggest TRPC3 as a potential target for pharmacological control of smooth muscle proliferation. Selectively inhibition of TRPC Ca(2+) entry channels in vascular smooth muscle is suggested as a promising strategy for in-stent restenosis prevention.