Regulation of Angiogenic Functions by Angiopoietins through Calcium-Dependent Signaling Pathways

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.

Autocrine release of angiopoietin-2 mediates cerebrovascular disintegration in Moyamoya disease

“…activated integrins, the focal adhesion kinase (FAK), the extracellular regulated kinase 1/2 (ERK1/2), or phosphatidylinositide 3-kinase (PI3K)/ Akt kinase signaling which are involved in cell proliferation, differentiation and motility. 37 Also, other barrier-destabilizing or pro-angiogenic molecules playing a role in the MMD pathology should be tested in our experimental setting. They might have an own impact on the disease or even interplay with angiopietin-2.…”

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

“…Finally, Tie1 is an orphan receptor which could reduce Tie2 phosphorylation and downstream signaling [7]. A recent investigation revealed that both ANG-1 and ANG-2 induce biphasic Ca 2+ signals in HUVEC by selectively promoting ER Ca 2+ release through InsP 3 R and RyR (Table 1) [217]. Of note, ANG-1-induced cell migration is sustained by InsP 3 R, while ANG-2 requires both InsP 3 R and RyR.…”

“…Of note, ANG-1-induced cell migration is sustained by InsP 3 R, while ANG-2 requires both InsP 3 R and RyR. However, while ANG-1 induces in vitro tubulogenesis in a Ca 2+ -dependent manner, intracellular Ca 2+ signaling is dispensable for ANG-2-induced tube formation [217]. Intriguingly, the lysosomal Ca 2+ pool, which is involved in VEGF-induced Ca 2+ signals [104], is not involved in the Ca 2+ response to ANG-1 and ANG-2 [217].…”

Hesperidin, a plant flavonoid accelerated the cutaneous wound healing in streptozotocin-induced diabetic rats: role of TGF-β/Smads and Ang-1/Tie2 signaling pathways

“…Angiopoietin 1 (Ang-1), a type of 70 kDa glycoprotein from angiopoietin family, serves as a ligand of the Tie receptor tyrosine kinase (Pafumi et al, 2015[ 86 ]). The phosphorylation of the Tie-1 receptor by Ang-1 initiates Ang-1-Tie signaling, and this Ang-1-Tie interaction resulted in its expression in endothelial cells where it plays a vital role in angiogenesis for development and regeneration (Dallabrida et al, 2005[ 30 ]; Jeansson et al, 2011[ 50 ]).…”