Decreased inspired oxygen stimulates de novo formation of coronary collaterals in adult heart

• Published in: Journal of molecular and cellular cardiology Vol. 150; pp. 1 - 11
• Main Authors: Aghajanian, Amir, Zhang, Hua, Buckley, Brian K., Wittchen, Erika S., Ma, Willa Y., Faber, James E.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.01.2021
• Subjects: Animals; Collateral Circulation - physiology; Collaterals; Coronary circulation; Coronary Vessels - physiopathology; Heart - physiopathology; Hypoxia; Hypoxia - physiopathology; Ischemic heart disease; Mice; Mice, Inbred C57BL; Myocardial Infarction - pathology; Myocardial Infarction - physiopathology; Myocardium - pathology; Oxygen - metabolism; Vascular Endothelial Growth Factor A - metabolism; Vascular Endothelial Growth Factor Receptor-2 - metabolism; VEGFR2; RFT; HBMVEC; CAD; FiO2; Coronary circulation; LAD; VEGFA; Ischemic heart disease; AAR; B6; RABEP2; Hypoxia; AMI; WT; Collaterals
• ISSN: 0022-2828; 1095-8584
• DOI: 10.1016/j.yjmcc.2020.09.015

Collateral vessels lessen myocardial ischemia when acute or chronic coronary obstruction occurs. It has long been assumed that although native (pre-existing) collaterals enlarge in obstructive disease, new collaterals do not form in the adult. However, the latter was recently shown to occur after coronary artery ligation. Understanding the signals that drive this process is challenged by the difficulty in studying collateral vessels directly and the complex milieu of signaling pathways, including cell death, induced by ligation. Herein we show that hypoxemia alone is capable of inducing collateral vessels to form and that the novel gene Rabep2 is required. Hypoxia stimulates angiogenesis during embryonic development and in pathological states. We hypothesized that hypoxia also stimulates collateral formation in adult heart by a process that involves RABEP2, a recently identified protein required for formation of collateral vessels during development. Exposure of mice to reduced FiO2 induced collateral formation that resulted in smaller infarctions following LAD ligation and that reversed on return to normoxia. Deletion of Rabep2 or knockdown of Vegfa inhibited formation. Hypoxia upregulated Rabep2, Vegfa and Vegfr2 in heart and brain microvascular endothelial cells (HBMVECs). Knockdown of Rabep2 impaired migration of HBMVECs. In contrast to systemic hypoxia, deletion of Rabep2 did not affect collateral formation induced by ischemic injury caused by LAD ligation. Hypoxia induced formation of coronary collaterals by a process that required VEGFA and RABEP2, proteins also required for collateral formation during development. Knockdown of Rabep2 impaired cell migration, providing one potential mechanism for RABEP2's role in collateral formation. This appears specific to hypoxia, since formation after acute ischemic injury was unaffected in Rabep2−/− mice. These findings provide a novel model for studying coronary collateral formation, and demonstrate that hypoxia alone can induce new collaterals to form in adult heart. [Display omitted] •Systemic hypoxemia stimulated de novo formation of coronary collaterals.•This was associated with smaller infarctions following ligation of the LAD artery.•Rabep2 was upregulated by hypoxia and required for hypoxic collateral formation.•Migration was impaired in Rabep2 depleted endothelial cells—one potential mechanism.•These findings provide a novel model for studying coronary collateral formation.