Down regulation of Jag-1 in VSMCs contributes to impaired angiogenesis under high glucose condition: Experimental study using aortic rings of rats

Article type: Research Article

Authors: Lee, Seahyoung^{a; b; 1} | Yu, Long-Hao^{c; 1} | Lim, La-Ri^d | Lim, Hee-Jung^d | Si, Jung-Eun^d | Ko, Young-Guk^{d; e; *} | Hwang, Ki-Chul^{a; b; *}

Affiliations: [a] Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung-si, Gangwon-do, Korea | [b] Catholic Kwandong University International St. Mary’s Hospital, Incheon Metropolitan City, Korea | [c] Department of Cardiology, The Fourth Hospital of Harbin Medical University, China | [d] Severance Integrative Research Institute for Cerebral and Cardiovascular Disease, Yonsei University Health System, Seoul, Korea | [e] Division of Cardiology, Yonsei University Health System, Seoul, Korea

Correspondence: [*] Corresponding author: Ki-Chul Hwang, PhD, Distinguished Professor, Director, Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung-si, Gangwon-do, 210-701, Korea. E-mail: kchwang@cku.ac.kr.

Correspondence: [*] Corresponding author: Young-Guk Ko, MD, PhD, Professor, Division of Cardiology, Severance Cardiovascular Hospital, Yonsei University Health System, Seoul 120-752, Korea. Tel.: +82 32 290 3883; Fax: +82 32 290 2774; ygko@yuhs.ac.

Note: [1] Co-first authors.

Abstract: The major cause of diabetes-related mortality is the complications involving aberrant angiogenesis. To understand the underlying mechanisms of such altered-angiogenesis in diabetes, examining the interaction between endothelial cells (ECs) and neighboring smooth muscle cells (VSMCs) rather than mainly focusing on EC might provide us useful information. Thus, in the present study, we examined the effect of high glucose on the expression of Jag1, one of the key trans-activating ligands of Notch receptors known to be involved in EC-SMC interaction, as well as angiogenic process, in vascular smooth muscle cells (VSMCs) to elucidate possible role of EC-VSMC interaction in diabetes-related angiopathy. Our data indicate that high glucose condition decreases the expression of Jag1 in VSMCs possibly by increasing Jag1-targeting micro RNAs (miRNAs) such as miR-21, and exogenous Jag1-simulating peptides increase proliferation and migration of ECs under high glucose condition in vitro. Ex vivo study using aortic rings from normal and streptozotocin (STZ)-treated diabetic mouse demonstrated that exogenous Jag1-simulating peptides increases EC sprouting of aortic rings from diabetic mouse under high glucose condition. Our data suggest that EC-VSMC interaction is altered under high glucose condition and restoring EC-VSMC interaction can be a feasible therapeutic target for treating diabetes-related angiopathy.

Keywords: High glucose, vascular smooth muscle cell, Jag-1, miR-21, Angiogenesis, aortic ring assay

DOI: 10.3233/CH-141915

Journal: Clinical Hemorheology and Microcirculation, vol. 61, no. 3, pp. 497-511, 2015