Rnd3/RhoE Modulates Hypoxia-Inducible Factor 1α/Vascular Endothelial Growth Factor Signaling by Stabilizing Hypoxia-Inducible Factor 1α and Regulates Responsive Cardiac Angiogenesis

Abstract

The insufficiency of compensatory angiogenesis in the heart of hypertension patients contributes to heart failure transition. The HIF1α-VEGF signaling cascade controls responsive angiogenesis. One of the challenges in reprograming the insufficient angiogenesis is to achieve a sustainable tissue exposure to the pro-angiogenic factors, such as HIF1α stabilization. In this study, we identified Rnd3, a small Rho GTPase, as a pro-angiogenic factor participating in the regulation of the HIF1α-VEGF signaling cascade. Rnd3 physically interacted with and stabilized HIF1α, and consequently promoted VEGFA expression and endothelial cell tube formation. To demonstrate this pro-angiogenic role of Rnd3 in vivo, we generated Rnd3 knockout mice. Rnd3 haploinsufficient (Rnd3+/−) mice were viable, yet developed dilated cardiomyopathy with heart failure after transverse aortic constriction stress. The post-stress Rnd3+/− hearts showed significantly impaired angiogenesis and decreased HIF1α and VEGFA expression. The angiogenesis defect and heart failure phenotype were partially rescued by cobalt chloride treatment, a HIF1α stabilizer, confirming a critical role of Rnd3 in stress-responsive angiogenesis. Furthermore, we generated Rnd3 transgenic mice and demonstrated that Rnd3 overexpression in heart had a cardio-protective effect through reserved cardiac function and preserved responsive angiogenesis after pressure overload. Finally, we assessed the expression levels of Rnd3 in the human heart and detected significant downregulation of Rnd3 in patients with end-stage heart failure. We concluded that Rnd3 acted as a novel pro-angiogenic factor involved in cardiac responsive angiogenesis through HIF1α-VEGFA signaling promotion. Rnd3 downregulation observed in heart failure patients may explain the insufficient compensatory angiogenesis involved in the transition to heart failure.

CtBP2 is associated with angiogenesis and regulates the apoptosis of prostate cancer cells

“…Meucci et al (29) identified that Axon guidance and focal adhesion pathways regulate cell motility, tumor invasion and angiogenesis leading to less aggressive tumors in older age patients. Dilated cardiomyopathy pathway is also reported to be related to angiogenesis (30).…”

Qiliqiangxin attenuates hypoxia‐induced injury in primary rat cardiac microvascular endothelial cells via promoting HIF‐1α‐dependent glycolysis

“…The fact that HIF‐1α is elevated under hypoxic conditions has been confirmed in most types of endothelial cells, for example, human/rat cardiac microvascular endothelial cells and human umbilical vein endothelial cells (HUVECs) 28, 29, 30. As is known, activated HIF‐1α and its downstream effector VEGF are key regulators which can protect endothelial cells from hypoxia‐induced impairment and promote angiogenesis and cell migration 7. In the present study, however, with long‐time hypoxia, the protective mechanism initiated by adaptive HIF‐1α elevation seems decompensated and not sufficient.…”

RhoJ promotes hypoxia induced endothelial‐to‐mesenchymal transition by activating WDR5 expression

“…RhoJ is known to play an essential role in angiogenesis, a process with which HIF‐1α is intimately involved, although it remains an unaddressed issue whether the ability of RhoJ to regulate angiogenesis relies on HIF‐1α . Indeed, mounting evidence suggests that small G proteins function to fine‐tune the activity of HIF‐1α in various settings by stabilizing HIF‐1α protein, by controlling HIF‐1α oligomerization, or by stimulating HIF‐1α expression . These findings collectively argue for a role for RhoJ in regulating the response to hypoxia, the up‐regulation of TWIST and SNAIL being part of it, in endothelial cells.…”