Endothelial Transient Receptor Potential Channels and Vascular Remodeling: Extracellular Ca2 + Entry for Angiogenesis, Arteriogenesis and Vasculogenesis

Abstract

Vasculogenesis, angiogenesis and arteriogenesis represent three crucial mechanisms involved in the formation and maintenance of the vascular network in embryonal and post-natal life. It has long been known that endothelial Ca²⁺ signals are key players in vascular remodeling; indeed, multiple pro-angiogenic factors, including vascular endothelial growth factor, regulate endothelial cell fate through an increase in intracellular Ca²⁺ concentration. Transient Receptor Potential (TRP) channel consist in a superfamily of non-selective cation channels that are widely expressed within vascular endothelial cells. In addition, TRP channels are present in the two main endothelial progenitor cell (EPC) populations, i.e., myeloid angiogenic cells (MACs) and endothelial colony forming cells (ECFCs). TRP channels are polymodal channels that can assemble in homo- and heteromeric complexes and may be sensitive to both pro-angiogenic cues and subtle changes in local microenvironment. These features render TRP channels the most versatile Ca²⁺ entry pathway in vascular endothelial cells and in EPCs. Herein, we describe how endothelial TRP channels stimulate vascular remodeling by promoting angiogenesis, arteriogenesis and vasculogenesis through the integration of multiple environmental, e.g., extracellular growth factors and chemokines, and intracellular, e.g., reactive oxygen species, a decrease in Mg²⁺ levels, or hypercholesterolemia, stimuli. In addition, we illustrate how endothelial TRP channels induce neovascularization in response to synthetic agonists and small molecule drugs. We focus the attention on TRPC1, TRPC3, TRPC4, TRPC5, TRPC6, TRPV1, TRPV4, TRPM2, TRPM4, TRPM7, TRPA1, that were shown to be involved in angiogenesis, arteriogenesis and vasculogenesis. Finally, we discuss the role of endothelial TRP channels in aberrant tumor vascularization by focusing on TRPC1, TRPC3, TRPV2, TRPV4, TRPM8, and TRPA1. These observations suggest that endothelial TRP channels represent potential therapeutic targets in multiple disorders featured by abnormal vascularization, including cancer, ischemic disorders, retinal degeneration and neurodegeneration.

Keywords: Ca2+ signaling; TRPC; TRPM; TRPV; endothelial cells; endothelial colony forming cells.

FIGURE 1

Vasculogenesis and angiogenesis are the main processes responsible for vascular remodeling. (A) Schematic representation of vasculogenesis, which consists in de novo aggregation of circulating endothelial progenitor cells (EPCs) into functional vessels. (B) Schematic representation of angiogenesis, the physiological process whereby capillaries give rise to neovessels to cope with oxygen and nutrient requirements. Angiogenesis may occur through two distinct mechanisms: sprouting angiogenesis and intussusceptive angiogenesis (see text for further details).

FIGURE 2

TRPC channels in angiogenesis. Representation of the main TRPC channels involved in angiogenesis. TRPC1 mediates angiogenesis after VEGF- (still debated), IGF-, bFGF- and thrombin-induced stimulation. TRPC4 is sensitive to EGF, oxLDL and hypoxia. TRPC3 responds to erythropoietin (EPO) and VEGF stimulation, such as TRPC6, which can be also activated by oxLDL, thrombin and 14,15-EETs. Finally, TRPC5 is sensitive to hypoxia, riluzole and oxLDL-dependent activation.

FIGURE 3

TRPV channels in angiogenesis. TRPV1, TRPV2, and TRPV4 are the main TRPV isoforms that mediate angiogenesis. TRPV1 is involved in angiogenesis in response to: VEGF, capsaicin, evodiamine, simvastatin, EPO, epigallocatechin-3-gallate, and 14,15-EETs. Shear stress-, cyclic strain-, 4α- PDD-, ROS-, AA- and GSK-mediated TRPV4 activation participate to angiogenesis. Finally, TRPV2 stimulation with lysophosphatidylcoline can play a role in this process.

FIGURE 4

TRPM and TRPA1 channels in angiogenesis. Some TRPM isoforms are shown to be involved in angiogenesis. In particular, TRPM2 stimulates angiogenesis after VEGF stimulation, whereas TRPM4 is activated by H2O2, stroke and oxygen-glucose deprivation. TRPM7 regulates endothelial cell proliferation and tube formation being sensitive to a reduction in intracellular Mg2⁺ concentration and to oxygen-glucose deprivation. Finally, TRPA1 promotes angiogenesis in response to AITC and upon simvastatin-dependent TRPV1 activation.