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 Ca 2+ 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 Ca 2+ 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 Ca 2+ 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 Mg 2+ 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.

TRPM2 channel-mediated cell death: An important mechanism linking oxidative stress-inducing pathological factors to associated pathological conditions

“…Some evidence also suggests that activation of mitochondrial NADase is another mechanism for H 2 O 2 -induced ADPR generation and TRPM2 channel activation [ 92 ]. Since early in vitro studies that established a role for the TRPM2 channel in conferring susceptibility to H 2 O 2 -induced cell death in human embryonic kidney (HEK) 293 cells expressing recombinant mammalian TRPM2 channels [ 31 , 33 , 89 ], extensive efforts have been directed towards examining the importance of endogenous TRPM2 channels in mammalian cells in coupling a wide spectrum of OS-inducing pathological factors, as discussed below, to their profound impacts on cellular functions and, furthermore, the pathogenesis and progression of associated pathological conditions [ 73 , 78 , [83] , [84] , [85] , 87 , [93] , [94] , [95] , [96] , [97] , [98] , [99] , [100] , [101] , [102] , [103] , [104] , [105] ].…”

Ion Channels as Therapeutic Targets in High Grade Gliomas

“…The entry of Ca 2+ through TRPM channels is essential for activating Ca 2+ -sensitive K + channels (KCa1.1), and initiating the machinery required for migration [ 11 ]. TRPC6 promotes glioma cell growth, clonogenicity and transition from g 2 /m phase of the cell cycle [ 98 ], proliferation and angiogenesis [ 99 ]. Similarly, suppression of TRPM7 inhibits the capacity of malignant gliomas cells to proliferate, migrate and invade [ 100 ].…”

Role of VEGF-A and LRG1 in Abnormal Angiogenesis Associated With Diabetic Nephropathy

“…Angiogenesis is a complex physiological process that involves the interaction between many angiogenic growth factors and endothelium and extracellular matrix ( Ucuzian et al, 2010 ). It requires endothelial cell (EC) proliferation, survival, migration, morphology changes, anastomoses, and extracellular matrix degeneration ( Negri et al, 2020 ). Angiogenesis is mediated by the delicate balance of stimulatory and inhibitory growth factors, while any disruption of these factors would give rise to abnormal angiogenesis with pathological outcomes.…”