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.

Keywords: TRPC channels.; basic fibroblast growth factor; endothelial cells; endothelial colony forming cells; inositol-1,4,5-trisphosphate; nicotinic acid adenine dinucleotide phosphate; store-operated Ca2+ entry; stromal derived factor-1α; vascular endothelial growth factor.