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Regulation of placenta growth factor by hemodynamics and reactive oxygen species

血流动力学和活性氧对胎盘生长因子的调节

基本信息

批准号：
7730752
负责人：
PAMELA C LOVERN
金额：
$ 35.26万
依托单位：
OKLAHOMA STATE UNIVERSITY STILLWATER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-17 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7730752
关键词：
Accounting Affect American Animal Model Animals Arteries Biological Biological Models Blood Vessels Blood flow Bypass Cardiovascular Diseases Cardiovascular system Cell Culture System Cell Culture Techniques Cells Clinical Clinical Research Coculture Techniques Combined Modality Therapy Complex Complications of Diabetes Mellitus Coronary Coronary Arteriosclerosis Data Defect Development Diabetes Mellitus Diagnosis Diet Disease Distal Dose Endothelial Cells Epoprostenol Experimental Models Face Fatty acid glycerol esters Functional disorder Future Generations Goals Growth Growth Factor Hydrogen Peroxide Hyperglycemia Hyperlipidemia In Vitro Knowledge Link Literature Measurement Measures Mediator of activation protein Messenger RNA Metabolic Metabolic syndrome Molecular Molecular and Cellular Biology Mus Nitric Oxide Outcome Oxidative Stress Patients Peripheral arterial disease Physiological Physiological Processes Placental Growth Factor Positioning Attribute Production Proteins Reactive Oxygen Species Regulation Research Risk Role Signal Pathway Signal Transduction Smooth Muscle Myocytes Streptozocin Techniques Testing Therapeutic Therapeutic Intervention Time Tissues Vascular Diseases Vascular Endothelial Cell Vascular Endothelial Growth Factors Work artery occlusion base design diabetic diabetic cardiomyopathy diabetic patient functional improvement hemodynamics improved in vivo in vivo Model innovation mortality mouse model mutant mouse model novel public health relevance research study response shear stress

项目摘要

DESCRIPTION (provided by applicant): Collateral artery enlargement (arteriogenesis) is a physiological process that can 'bypass' atherosclerotic supply arteries to preserve blood flow to distal tissue. Thus, pharmacological stimulation of arteriogenesis could be highly beneficial in the treatment of ischemic vascular diseases, such as coronary artery disease (CAD) and peripheral artery disease (PAD). Such treatments would be especially valuable in the setting of diabetes, which both 1) severely increases the risk of CAD and PAD and 2) inhibits native (unstimulated) arteriogenesis. Placenta growth factor (PlGF, PGF) is a VEGF-related growth factor that specifically favors the expansion of arteries via arteriogenesis. Thus, therapeutic stimulation of PlGF expression could potentially be used to enhance arteriogenesis and improve clinical outcomes in patients with CAD and PAD. However, such treatments are not currently possible, due to a lack of understanding of the basic mechanism(s) regulating PlGF expression. Our preliminary data suggests the existence of a novel mechanism regulating PlGF expression in the vascular wall. Moreover, our evidence suggests that this mechanism is dysfunctional in diabetes. Thus, dysregulation of PlGF expression may contribute to faulty arteriogenesis in diabetics. The LONG TERM GOAL of this research is to elucidate key mechanisms regulating PlGF expression under physio- and patho-physiological conditions. This project will pursue three Specific Aims. Specific Aim 1: Establish the basic regulatory mechanism controlling PlGF expression in the vascular wall. These studies will be performed in three complementary model systems: primary vascular smooth muscle cells (SMC) in static culture; co- cultured vascular endothelial cells (EC) and SMC which are exposed to shear stress; and isolated perfused mouse vessels. Specific Aim 2: Identify key steps in the basic PlGF regulatory mechanism that are altered by diabetes. These studies will confirm the physiological relevance of the mechanism(s) uncovered in Aim 1. These experiments will be conducted in mouse models of hyperglycemia (streptozotocin treatment), hyperlipidemia (high-fat diet treatment) and combined hyperglycemia/hyperlipidemia. This design will allow us 1) to determine what facet of the complex metabolic dysfunction that typically occurs in diabetes inhibits PlGF expression, and 2) to pinpoint the regulatory step at which inhibition of PlGF expression occurs. Specific Aim 3: Assess the ability of enhanced endogenous PlGF expression to stimulate arteriogenesis. These studies will take the results of Aim 2 to the next level by determining whether correction of the signaling defect revealed in Aim 2 can 1) reverse the inhibition of PlGF expression in diabetes, and 2) result in functional improvement as measured by capacity to undergo arteriogenesis in response to vascular occlusion. These innovative and novel studies will provide essential new information about the regulation of an important arteriogenic factor and will provide "proof of concept" for the idea that normalizing or enhancing PlGF expression can improve the arteriogenic response to vascular occlusion (due to CAD or PAD) in patients with diabetes. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE Ischemic cardiovascular diseases (CVD) such as coronary artery disease are highly prevalent in diabetics and account for most of the mortality in this patient group. Stimulation of collateral artery growth (arteriogenesis) to create a physiological "bypass" is a promising treatment concept; however, greater understanding of the mechanisms controlling arteriogenesis is needed before such treatments are a reality. This research will investigate fundamental mechanisms regulating the key arteriogenic growth factor PlGF as a basis for developing new, noninvasive treatments for ischemic CVD.

描述（由申请人提供）：