Endothelial TRPV1 as an Emerging Molecular Target to Promote Therapeutic Angiogenesis

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.

Therapeutic Potential of Endothelial Colony-Forming Cells in Ischemic Disease: Strategies to Improve their Regenerative Efficacy

“…This strategy permits stimulating circulating ECFCs with no need of viral manipulation (as required by conventional optogenetics) and with unprecedented spatial and temporal resolution. Thus, it has been proposed that the injection of infrared-sensitive biocompatible and photosensitive nanoparticles combined with the local implantation of a source of visible light could represent a promising solution to treat ischemic disorders by recruiting resident ECFCs [ 188 ].…”

“…In turn, KLF2 is a transcription factor that mediates ECFC differentiation and supports ECFCs-mediated neovascularization [ 187 ]. Furthermore, EPO has been shown to stimulate neovessel growth in murine models of hindlimb ischemia by promoting extracellular Ca 2+ influx through Transient Receptor Potential Vanilloid 1 (TRPV1) [ 188 ]. ECFC priming with EPO significantly improved their regenerative outcome following MCAO.…”

Towards Novel Geneless Approaches for Therapeutic Angiogenesis

“…Endothelial cells use TRP channels to sense the local microenvironment in which they reside, thereby adapting to subtle changes in the chemical composition of the extracellular milieu and/or in the mechanical forces acting on the vascular wall ( Genova et al, 2020 ; Negri et al, 2020a ). For instance, the endothelial TRPV1 is sensitive to an increase in local temperature above 43°C ( Negri et al, 2020b ) and/or in local hydrogen peroxide (H 2 O 2 ; DelloStritto et al, 2016 ), whereas TRPV4 is sensitive to physical stimuli, such as shear stress ( Schierling et al, 2011 ) and pulsatile stretch ( Thodeti et al, 2009 ), and to arachidonic acid (AA) production ( Fiorio Pla et al, 2008 ). Recent studies suggested that TRP channels may also stimulate ECFCs’ angiogenic activity.…”

“…Indeed, reduction of the oxygen present in the extracellular medium in consequence to the polymer photoexcitation leads to the formation of superoxide (O 2 − ), intermediate ROS and ends up with spatially and temporally controlled generation of H 2 O 2 , which, in turn, can permeate the plasma membrane, thereby causing an increase in the cytosolic H 2 O 2 levels, which can activate TRPV1 and induced extracellular Ca 2+ entry ( DelloStritto et al, 2016 ; Lodola et al, 2019a ). A local reduction in extracellular pH because of polymer photoexcitation could also gate TRPV1 ( Negri et al, 2020b ), but its role in P3HT-mediated TRPV1 activation remains to be investigated.…”

Therapeutic Potential of Endothelial Colony Forming Cells in Ischemic Disease: Strategies to Improve Their Regenerative Efficacy

“…KLF2, in turn, is a transcription factor that mediates ECFC differentiation and supports ECFCs-mediated neovascularization [205]. Furthermore, EPO has been shown to stimulate neovessel growth in murine models of hindlimb ischemia by promoting extracellular Ca 2+ influx through Transient Receptor Potential Vanilloid 1 (TRPV1) [206,207]. ECFCs priming with EPO significantly improved their regenerative outcome following MCAO.…”