Endothelial Ca2+ Signaling, Angiogenesis and Vasculogenesis: Just What It Takes to Make a Blood Vessel

Abstract

It has long been known that endothelial Ca2+ signals drive angiogenesis by recruiting multiple Ca2+-sensitive decoders in response to pro-angiogenic cues, such as vascular endothelial growth factor, basic fibroblast growth factor, stromal derived factor-1α and angiopoietins. Recently, it was shown that intracellular Ca2+ signaling also drives vasculogenesis by stimulation proliferation, tube formation and neovessel formation in endothelial progenitor cells. Herein, we survey how growth factors, chemokines and angiogenic modulators use endothelial Ca2+ signaling to regulate angiogenesis and vasculogenesis. The endothelial Ca2+ response to pro-angiogenic cues may adopt different waveforms, ranging from Ca2+ transients or biphasic Ca2+ signals to repetitive Ca2+ oscillations, and is mainly driven by endogenous Ca2+ release through inositol-1,4,5-trisphosphate receptors and by store-operated Ca2+ entry through Orai1 channels. Lysosomal Ca2+ release through nicotinic acid adenine dinucleotide phosphate-gated two-pore channels is, however, emerging as a crucial pro-angiogenic pathway, which sustains intracellular Ca2+ mobilization. Understanding how endothelial Ca2+ signaling regulates angiogenesis and vasculogenesis could shed light on alternative strategies to induce therapeutic angiogenesis or interfere with the aberrant vascularization featuring cancer and intraocular disorders.

Transient Receptor Potential Canonical (TRPC) Channels as Modulators of Migration and Invasion

“…Furthermore, phosphatase and tensin homolog (PTEN) regulates TRPC6 activation and subsequent promotion of angiogenesis in primary human pulmonary artery endothelial cells (HPAEs) [118]. As several comprehensive reviews regarding TRP channels and angiogenesis have recently been published, we recommend the readers to turn to these for further information [119][120][121].…”

Type 2 Diabetes Alters Intracellular Ca2+ Handling in Native Endothelium of Excised Rat Aorta

“…The pharmacological manipulation of the Ca 2+ response to low (i.e., 20 µM) and high (i.e., 300 µM) doses of ATP strongly suggested that SERCA-dependent Ca 2+ removal from the cytosol is compromised in in situ aorta of OZDF rats. The inhibition of SERCA-dependent Ca 2+ clearance could be due to the down-regulation of SERCA2B, the main endothelial SERCA isoform [46], and/or to the slowing down of its activity. Previous work has revealed that, while SERCA2 protein is up-regulated by type 2 diabetes mellitus, its clearing rate may be severely compromised.…”

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

“…Endothelial cells line the inner lumen of blood vessels and are, therefore, exposed to a myriad of chemical (e.g., growth factors and chemokines) and physical (e.g., laminar shear stress and pulsatile stretch) cues, which must be properly perceived for the maintenance of tissue homeostasis (Moccia et al, 2012a(Moccia et al, , 2019b. TRP channels represent the most suitable signal transduction pathway whereby vascular endothelial cells integrate such a vast array of extracellular stimuli due to the versatility of their gating mechanisms.…”

“…Endothelial TRP channels have long been associated to angiogenesis and vascular remodeling due to their ability to engage intracellular signaling pathways associated to endothelial cell proliferation, migration, adhesion, tubulogenesis, and permeability (Moore et al, 1998;Fantozzi et al, 2003;Cheng et al, 2006). Endothelial TRP channels may control angiogenesis by mediating Ca 2+ entry in response to extracellular growth factors, such as VEGF and bFGF, that are liberated in peripheral circulation upon an ischemic insult or by growing tumors (Moccia et al, 2019b). Alternately, TRP channels sense cellular stress factors, such as an increase in ROS production or a decrease in Mg 2+ levels, or an increase in laminar shear stress, which ultimately stimulates arteriogenesis (Moccia and Guerra, 2016).…”

“…Endothelial TRPC channels sustain angiogenesis by sustaining the Ca 2+ response to pro-angiogenic cues, including VEGF, bFGF, and insulin-like growth factor 1 (IGF-1), and/or by detecting subtle changes in the composition of the local microenvironment, and/or in response to small molecule drugs (Smani et al, 2018;Moccia et al, 2019b). While the mechanisms whereby TRPC3, TRPC4, TRPC5 and TRPC6 control angiogenesis has been largely understood, the role of TRPC1 is still shrouded in mystery.…”