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
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Zeng, Heng; Li, Lanfang; Chen, Jian-Xiong (2014) Loss of Sirt3 limits bone marrow cell-mediated angiogenesis and cardiac repair in post-myocardial infarction. PLoS One 9:e107011
Li, Lanfang; Zeng, Heng; Hou, Xuwei et al. (2013) Myocardial injection of apelin-overexpressing bone marrow cells improves cardiac repair via upregulation of Sirt3 after myocardial infarction. PLoS One 8:e71041
Chen, Jian-Xiong; Tuo, Qinhui; Liao, Duan-Fang et al. (2012) Inhibition of protein tyrosine phosphatase improves angiogenesis via enhancing Ang-1/Tie-2 signaling in diabetes. Exp Diabetes Res 2012:836759
Chen, Jian-Xiong; Zeng, Heng; Reese, Jeff et al. (2012) Overexpression of angiopoietin-2 impairs myocardial angiogenesis and exacerbates cardiac fibrosis in the diabetic db/db mouse model. Am J Physiol Heart Circ Physiol 302:H1003-12
Tuo, Qin-hui; Xiong, Guo-zuo; Zeng, Heng et al. (2011) Angiopoietin-1 protects myocardial endothelial cell function blunted by angiopoietin-2 and high glucose condition. Acta Pharmacol Sin 32:45-51