Abstract
Therapeutic angiogenesis represents an emerging strategy to treat ischemic diseases by stimulating blood vessel growth to rescue local blood perfusion. Therefore, injured microvasculature may be repaired by stimulating resident endothelial cells or circulating endothelial colony forming cells (ECFCs) or by autologous cell-based therapy. Endothelial Ca2+ signals represent a crucial player in angiogenesis and vasculogenesis; indeed, several angiogenic stimuli induce neovessel formation through an increase in intracellular Ca2+ concentration. Several members of the Transient Receptor Potential (TRP) channel superfamily are expressed and mediate Ca2+-dependent functions in vascular endothelial cells and in ECFCs, the only known truly endothelial precursor. TRP Vanilloid 1 (TRPV1), a polymodal cation channel, is emerging as an important player in endothelial cell migration, proliferation, and tubulogenesis, through the integration of several chemical stimuli. Herein, we first summarize TRPV1 structure and gating mechanisms. Next, we illustrate the physiological roles of TRPV1 in vascular endothelium, focusing our attention on how endothelial TRPV1 promotes angiogenesis. In particular, we describe a recent strategy to stimulate TRPV1-mediated pro-angiogenic activity in ECFCs, in the presence of a photosensitive conjugated polymer. Taken together, these observations suggest that TRPV1 represents a useful target in the treatment of ischemic diseases.
Highlights
The interior of blood vessels is lined by endothelial cells, which integrate chemical and physical stimuli deriving from circulating blood and surrounding tissues to redirect blood flow according to local energy requirements [1,2]
While excessive vascularization is associated with tumorigenesis, intraocular and inflammatory diseases, and pulmonary arterial hypertension (PAH) [7,8], insufficient vessel growth or impaired blood flow due to vessel obstruction may lead to severe ischemic disorders, including stroke, peripheral artery disease (PAD), pre-eclampsia, acute myocardial infarction (AMI), and ischemic retinopathies, as well as to neurodegeneration [9,10]
These treatments did not affect either VEGF-induced intracellular Ca2+ signals or tubular network formation. These findings clearly demonstrated that TRP Vanilloid 1 (TRPV1) activation per se is able to deliver a pro-angiogenic Ca2+ signal to vascular endothelial cells [89]
Summary
The interior of blood vessels is lined by endothelial cells, which integrate chemical and physical stimuli deriving from circulating blood and surrounding tissues to redirect blood flow according to local energy requirements [1,2]. An additional endothelial Ca2+ entry route is provided by the superfamily of non-selective Transient Receptor Potential (TRP) cation channels, which comprises 28 members [18,34,35] Standard nomenclature grouped these 28 members in six subfamilies, based on their sequence homology: canonical (TRPC1-7), vanilloid (TRPV1-6), melastatin (TRPM1-8), ankyrin (TRPA1), mucolipin (TRPML1-3), and polycystin (TRPP). It has been suggested that the reparative phenotype of autologous ECFCs could be rejuvenated by transduction with TRPC3 [47], which remarkably increases the pro-angiogenic Ca2+ response to VEGF [26,48] Based on this rationale, we discuss the hypothesis to exploit chemical and physical stimuli to target endothelial TRPV1 for regenerative purposes. These evidences hint at TRPV1 as a promising molecular tool to favor post-ischemic revascularization
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