Endothelial Calcium Machinery and Angiogenesis: Understanding Physiology to Interfere with Pathology

Abstract

Endothelial cells (ECs) play a pivotal role in physiological and altered tissue neovascularization. They face multiple morphological, biochemical and functional changes during the different phases of angiogenesis, under the regulation of a great number of proangiogenic and antiangiogenic signals, including soluble and insoluble factors, cell-cell and cell-matrix interactions. ECs mutual contacts (and also interactions with other cell types, such as pericytes and smooth vascular muscle cells), motility, proliferation, apoptosis and differentiation are all calcium-dependent events finely tuned in space and time. Most of the angiogenic-related peptidic factors (VEGF, bFGF and others) promote an increase of cytosolic free calcium concentration in ECs, giving rise to calcium-activated intracellular cascades engaged in the different steps of the angiogenic process. A better knowledge of such signals could allow to set new diagnostic and therapeutical approaches aimed to interfere with altered neovascularization, particularly during cancer progression. This review reports the state of the art about endothelial angiogenic-related calcium signaling and discusses the most attractive perspectives for the future.

A cellular Potts model analyzing differentiated cell behavior during in vivo vascularization of a hypoxic tissue

“…In particular, angiogenic factors have been widely demonstrated to activate a number of downstream intracellular cascades which control the behavior and the biophysical properties of vascular cells [33]. Among them, a fundamental role is played by calcium signaling pathways, as reported in great details in the experimental literature, see for instance [40,41,42] and references therein.…”

Multiple Roles of Protein Kinase A in Arachidonic Acid–Mediated Ca2+ Entry and Tumor-Derived Human Endothelial Cell Migration

“…NO mediates the function of many angiogenic factors and interferes with their expression. Furthermore, NO, through cyclic guanosine 3′,5′-monophosphate (cGMP)-dependent and cGMP-independent pathways, is able to regulate different types of calciumpermeable channels in ECs (1,2,4,(13)(14)(15)(16)(17)(18)(19)(20). In this context, we previously reported a crosstalk between arachidonateactivated calcium signals and NO metabolism (6).…”

“…These pathways promote store-operated and non-store-operated Ca 2+ entry (SOCE and NSOCE, respectively) from extracellular medium into endothelial cells (EC;refs. 3,4).…”

An Innovative Assay for the Analysis of In Vitro Endothelial Remodeling: Experimental and Computational Evidence

“…The overall process is largely mediated by the redundant activity of soluble and fixed environmental factors, respectively including growth factors, such as VEGFs and FGF, and extracellular matrix (ECM) components, such as collagen, fibronectin and gelatin (Munaron 2006;Dister et al, 2003;Munaron et al, 2000). In particular, the dynamic interactions between microvascular endothelial cells (EC) and ECM proteins are mediated by integrins, a superfamily of cell surface receptors whose selective recruitment regulates the angiogenic process.…”