Abstract
Angiopoietins are vascular factors essential for blood vessel assembly and correct organization and maturation. This study describes a novel calcium-dependent machinery activated through Angiopoietin-1/2-Tie receptor system in HUVECs monolayer. Both cytokines were found to elicit intracellular calcium mobilization. Targeting intracellular Ca2+ signaling, antagonizing IP3 with 2-APB or cADPR with 8Br-cADPR, was found to modulate in vitro angiogenic responses to Angiopoietins in a specific way. 2-APB and 8Br-cADPR impaired the phosphorylation of AKT and FAK induced by Ang-1 and Ang-2. On the other hand, phosphorylation of ERK1/2 and p38, as well as cell proliferation, was not affected by either inhibitor. The ability of ECs to migrate following Angs stimulation, evaluated by “scratch assay,” was reduced by either 2-APB or 8Br-cADPR following Ang-2 stimulation and only slightly affected by 2-APB in cells stimulated with Ang-1. These results identify a novel calcium-dependent machinery involved in the complex interplay regulating angiogenic processes showing that IP3- and cADPR-induced Ca2+ release specifically regulates distinct Angs-mediated angiogenic steps.
Highlights
Angiogenesis is a complex remodeling process characterized by the sprouting of new blood vessels from preexisting ones, occurring mainly during embryonic development and in pathological processes such as cancer
We have previously demonstrated that histamine H1 receptors mediate nicotinic acid adenine-dinucleotide phosphate (NAADP)-dependent Ca2+ signaling in endothelial cells (ECs) [31] and have recently identified that in Human umbilical vein endothelial cells (HUVECs) vascular endothelial growth factor (VEGF) increases [Ca2+]i by mobilizing Ca2+
We identify a novel pathway for Angs-Tie signaling whereby receptor activation leads to IP3- and cADPRdependent Ca2+ release and show that each of these Ca2+
Summary
Angiogenesis is a complex remodeling process characterized by the sprouting of new blood vessels from preexisting ones, occurring mainly during embryonic development and in pathological processes such as cancer. Experimental evidence identifies the Angs and their Tie receptors as important regulators of tumorinduced angiogenesis and metastasis [3, 4]. A major effort in the field of angiogenesis control has centered on the VEGF-VEGF receptor system [5, 6]. Despite partial success, resistance to anti-VEGF therapy, resulting from a variety of mechanisms, remains a major obstacle [7,8,9]. The search for novel key downstream effectors as a possible common “signaling hub” between Angs and other known growth factors is of potential significance in the perspective of angiogenesis control in cancer
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