Progressive Attenuation of Myocardial Vascular Endothelial Growth Factor Expression Is a Seminal Event in Diabetic Cardiomyopathy

Abstract

Background-Diabetic cardiomyopathy (DCM) is characterized by microvascular pathology and interstitial fibrosis, which leads to progressive heart failure; however, the pathogenesis of DCM remains uncertain. Methods and Results-Using the streptozotocin-induced diabetic rat model, we evaluated the natural course of DCM over a period of 1 year by serial echocardiography, Western blot analysis for vascular endothelial growth factor (VEGF), endothelial progenitor cell assays, myocardial blood flow measurements, and histopathologic analysis that included terminal dUTP nick end-labeling (TUNEL), capillary and cardiomyocyte density, and fibrosis area. Downregulation of myocardial VEGF expression preceded all other features of DCM and was followed by increased apoptosis of endothelial cells, decreased numbers of circulating endothelial progenitor cells, decreased capillary density, and impaired myocardial perfusion. Apoptosis and necrosis of cardiomyocytes ensued, along with fibrosis and progressive diastolic and then systolic dysfunction. To provide further evidence of the central role of VEGF in the pathophysiology of DCM, we replenished myocardial VEGF expression using naked DNA gene therapy via direct intramyocardial injection of plasmid DNA encoding VEGF (phVEGF 165 ). VEGF-replenished rats showed increased capillary density, decreased endothelial cell and cardiomyocyte apoptosis, and in situ differentiation of bone marrow-derived endothelial progenitor cells into endothelial cells. These anatomic findings were accompanied by significant improvements in cardiac function. Conclusions-These

Coronary vein infusion of multipotent stromal cells from bone marrow preserves cardiac function in swine ischemic cardiomyopathy via enhanced neovascularization

“…[24][25][26] Disruption of the balance between myocyte growth and angiogenesis leads to contractile dysfunction and heart failure. VEGF plays a critical role in this process.…”

Downregulation of connexin40 is associated with coronary endothelial cell dysfunction in streptozotocin-induced diabetic mice

“…It has been reported that capillary density in the heart is progressively decreased in Type 1 and Type 2 diabetic animal models, as well as in human diabetic patients (5,23,25,47,55). Decreased density of capillaries is due to loss of existing capillary network and attenuated regeneration of new capillaries.…”

Polymeric gene delivery of ischemia-inducible VEGF significantly attenuates infarct size and apoptosis following myocardial infarct

“…21 As diabetic patients with ischemic cardiomyopathy develop progressive congestive heart failure, however, local myocyte-secreted tissue VEGF levels begin to fall, further exacerbating the declining ventricular function seen in these patients. 11 In our rabbit model, with ligation of the proximal circumflex coronary artery, an infarction of the lateral wall of the left ventricle is produced. On the endocardial surface of the heart, this infarction is reliably centered at the base of the papillary muscles.…”

“…10 It is thought that local decreases in myocyte-secreted tissue VEGF contribute to as yet unspecified mechanisms of ischemic heart failure, especially in diabetes. 11 We have demonstrated earlier the ability of TERPLEXmediated plasmid VEGF gene therapy to ameliorate the detrimental effects of coronary occlusion on left ventricular function and to promote functional recovery following myocardial infarction. 12 Unregulated expression, however, limits the efficacy and safety of VEGF gene therapy within the myocardium.…”