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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.
Highlights
Blood vessel formation is an obligate requirement during embryonic development to nourish the cells of the rapidly expanding embryo with oxygen (O2) and nutrients and to remove their catabolic waste (Fischer et al, 2006; Udan et al, 2013)
Endothelial Transient Receptor Potential (TRP) channels serve a crucial role in vascular remodeling by regulating angiogenesis, arteriogenesis and vasculogenesis
The remarkable heterogeneity in their gating mechanisms, which can be further increased by the propensity of some isoforms to assemble into heteromeric complexes, render TRP channels the most versatile Ca2+ entry pathway in vascular endothelial cells, endothelial colony forming cells (ECFCs) and myeloid angiogenic cells (MACs)
Summary
Blood vessel formation is an obligate requirement during embryonic development to nourish the cells of the rapidly expanding embryo with oxygen (O2) and nutrients and to remove their catabolic waste (Fischer et al, 2006; Udan et al, 2013). Known as vasculogenesis and angiogenesis (Figure 1), are involved in the formation and maintenance of the vascular network both in the developing embryo and during postnatal life (Chung and Ferrara, 2011; Potente et al, 2011). Subsequent expansion and remodeling of nascent capillary plexus requires the engagement of the angiogenic process, which may be distinguished into sprouting angiogenesis and intussusceptive angiogenesis (Figure 1B) (Fischer et al, 2006; Chung and Ferrara, 2011; Potente et al, 2011). The TRP channel superfamily of non-selective cation channels comprises 28 members that are subdivided in six subfamilies by sequence homology: TRP Canonical (TRPC1-7), TRP Vanilloid (TRPV1-6), TRP Melastatin (TRPM1-8), TRP Ankyrin 1 (TRPA1), TRP Mucolipin (TRPM1-3), and TRP Polycystin
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