Impairment of myocardial angiogenesis and coronary collateral growth may contribute to high mortality in diabetic myocardial infarction. Our long-term goal is to define the molecular mechanism(s) responsible for abnormal vascular maturation and impairment of angiogenesis in the diabetic hearts. This revised proposal will investigate a possible disruption in the angiopoietins (Ang)/Tie-2 and apelin pathway in abnormal diabetes- associated vascular maturation and capillary regression. Our laboratory has shown a sustained increase in angiopoietin-2 (Ang-2) and prolyl hydroxylase-2 (PHD2) expression, and reduced Ang-1/Tie-2 and HIF- 11/apelin expression in diabetic mice. Our previous demonstration of impaired myocardial vessel maturation in diabetic mice;implicate that disruption of angiopoietins/Tie-2 system in favor of Ang-2, which leading to immature vessel formation and capillary regression, might be a novel mechanism responsible for impaired angiogenesis in diabetic hearts. Our overall hypothesis is that diabetes disrupts Ang-1/Tie-2 and apelin pathway by a mechanism involving Ang-2 and PHD2 activation;and these abnormalities lead to abnormal vascular maturation and capillary regression in diabetic hearts.
Specific Aim 1 will define the mechanism(s) by which hyperglycemia interferes with vascular maturation and capillary regression with a focus on the role of Ang-2 in the disruption of Ang-1/Tie-2 and apelin pathway. Using heart microvascular endothelial cells (EC), co-cultured EC-SMC spheroids and mouse aortic explants isolated from wild type (WT) or diabetic db/db mice, we will determine whether: (i) high glucose-induced excess of Ang-2 disrupts Ang-1/Tie-2 signaling and attenuates Ang-1-induced apelin expression;and (ii) interactions between Ang-2 and apelin are critical for the regulation of angiogenesis and vascular regression under high glucose conditions.
In specific aim 2, we will determine the role of Ang-2 and PHD2 activation in diabetes-associated disruption of vascular maturation and angiogenesis and promotion of vessel regression in an in vivo model of myocardial ischemia. Using Ang-2 deficient and PHD2 conditional knockout diabetic mice models, we will determine whether deficiency of Ang-2 or endothelial cell deletion of PHD2 rescues impaired apelin expression, normalizes immature neovessels, and improves myocardial angiogenesis.
In specific aim 3, we will further determine whether systemic administration of apelin rescues impaired angiogenic signaling, normalizes immature neovessels, and increases myocardial angiogenesis in diabetic hearts. Our studies will provide a framework for the development of a targeted therapeutic reduction in Ang-2 and PHD2 activation to ameliorate or reverse the abnormalities in diabetic vessel maturation and angiogenesis that characterizes the diabetic state.

Public Health Relevance

Impairment of myocardial angiogenesis and coronary collateral growth has contributed to high mortality in diabetic patients. The long-term objectives of this proposal are to explore the molecular mechanisms and novel pathways of hyperglycemia-induced disruption of the angiopoietins/Tie-2 and apelin/APJ interaction that contributes to the abnormal myocardial vasculature maturation and angiogenesis in diabetes. Our proposed studies should provide a framework for developing new therapeutic strategies for the treatment of diabetic impaired collateralization and angiogenesis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL102042-04
Application #
8588964
Study Section
Vascular Cell and Molecular Biology Study Section (VCMB)
Program Officer
Gao, Yunling
Project Start
2010-07-15
Project End
2014-11-30
Budget Start
2013-12-01
Budget End
2014-11-30
Support Year
4
Fiscal Year
2014
Total Cost
$331,909
Indirect Cost
$109,159
Name
University of Mississippi Medical Center
Department
Pharmacology
Type
Schools of Medicine
DUNS #
928824473
City
Jackson
State
MS
Country
United States
Zip Code
39216
Chen, Jian-Xiong; Chen, Sean T; Tao, Yong-Kang (2017) Cardiac pericyte is promising target for ischemic heart diseases: Role of Notch3. Int J Cardiol 246:57
Tao, Yong-Kang; Zeng, Heng; Zhang, Guo-Qiang et al. (2017) Notch3 deficiency impairs coronary microvascular maturation and reduces cardiac recovery after myocardial ischemia. Int J Cardiol 236:413-422
He, Xiaochen; Zeng, Heng; Chen, Sean T et al. (2017) Endothelial specific SIRT3 deletion impairs glycolysis and angiogenesis and causes diastolic dysfunction. J Mol Cell Cardiol 112:104-113
Wang, Shuo; Zeng, Heng; Chen, Sean T et al. (2017) Ablation of endothelial prolyl hydroxylase domain protein-2 promotes renal vascular remodelling and fibrosis in mice. J Cell Mol Med 21:1967-1978
Wang, Shuo; Zeng, Heng; Xie, Xue-Jiao et al. (2016) Loss of prolyl hydroxylase domain protein 2 in vascular endothelium increases pericyte coverage and promotes pulmonary arterial remodeling. Oncotarget 7:58848-58861
He, Xiaochen; Zeng, Heng; Chen, Jian-Xiong (2016) Ablation of SIRT3 causes coronary microvascular dysfunction and impairs cardiac recovery post myocardial ischemia. Int J Cardiol 215:349-57
Zeng, Heng; He, Xiaochen; Tuo, Qin-Hui et al. (2016) LPS causes pericyte loss and microvascular dysfunction via disruption of Sirt3/angiopoietins/Tie-2 and HIF-2?/Notch3 pathways. Sci Rep 6:20931
Zeng, Heng; Vaka, Venkata Ramana; He, Xiaochen et al. (2015) High-fat diet induces cardiac remodelling and dysfunction: assessment of the role played by SIRT3 loss. J Cell Mol Med 19:1847-56
Hou, Xuwei; Zeng, Heng; He, Xiaochen et al. (2015) Sirt3 is essential for apelin-induced angiogenesis in post-myocardial infarction of diabetes. J Cell Mol Med 19:53-61
Hou, Xuwei; Zeng, Heng; Tuo, Qin-Hui et al. (2015) Apelin Gene Therapy Increases Autophagy via Activation of Sirtuin 3 in Diabetic Heart. Diabetes Res (Fairfax) 1:84-91

Showing the most recent 10 out of 20 publications