Progressive attenuation of myocardial vascular endothelial growth factor expression is a seminal event in diabetic cardiomyopathy

Restoration of microvascular homeostasis and recovery of cardiac function in diabetic cardiomyopathy after replenishment of local vascular endothelial growth factor

Youngsup Yoon, Shigeki Uchida, Osamu Masuo, Manfred Cejna, Jong Seon Park, Hyeon Cheol Gwon, Rudolf Kirchmair, Ferdinand Bahlman, Dirk Walter, Cynthia Curry, Allison Hanley, Jeffrey M. Isner, Douglas W. Losordo

Research output: Contribution to journalArticle

231 Citations (Scopus)

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 (phVEGF165). 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 findings suggest that downregulation of VEGF may compromise microvascular homeostasis in the myocardium and thereby play a central role in the pathogenesis of DCM.

Original languageEnglish
Pages (from-to)2073-2085
Number of pages13
JournalCirculation
Volume111
Issue number16
DOIs
Publication statusPublished - 2005 Apr 26

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Diabetic Cardiomyopathies
Recovery of Function
Vascular Endothelial Growth Factor A
Homeostasis
Cardiac Myocytes
Fibrosis
Endothelial Cells
Apoptosis
Genetic Therapy
Down-Regulation
Streptozocin
Echocardiography
Myocardium
Plasmids
Necrosis
Heart Failure
Perfusion
Cell Count
Bone Marrow
Western Blotting

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Yoon, Youngsup ; Uchida, Shigeki ; Masuo, Osamu ; Cejna, Manfred ; Park, Jong Seon ; Gwon, Hyeon Cheol ; Kirchmair, Rudolf ; Bahlman, Ferdinand ; Walter, Dirk ; Curry, Cynthia ; Hanley, Allison ; Isner, Jeffrey M. ; Losordo, Douglas W. / Progressive attenuation of myocardial vascular endothelial growth factor expression is a seminal event in diabetic cardiomyopathy : Restoration of microvascular homeostasis and recovery of cardiac function in diabetic cardiomyopathy after replenishment of local vascular endothelial growth factor. In: Circulation. 2005 ; Vol. 111, No. 16. pp. 2073-2085.
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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 (phVEGF165). 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 findings suggest that downregulation of VEGF may compromise microvascular homeostasis in the myocardium and thereby play a central role in the pathogenesis of DCM.",
author = "Youngsup Yoon and Shigeki Uchida and Osamu Masuo and Manfred Cejna and Park, {Jong Seon} and Gwon, {Hyeon Cheol} and Rudolf Kirchmair and Ferdinand Bahlman and Dirk Walter and Cynthia Curry and Allison Hanley and Isner, {Jeffrey M.} and Losordo, {Douglas W.}",
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Progressive attenuation of myocardial vascular endothelial growth factor expression is a seminal event in diabetic cardiomyopathy : Restoration of microvascular homeostasis and recovery of cardiac function in diabetic cardiomyopathy after replenishment of local vascular endothelial growth factor. / Yoon, Youngsup; Uchida, Shigeki; Masuo, Osamu; Cejna, Manfred; Park, Jong Seon; Gwon, Hyeon Cheol; Kirchmair, Rudolf; Bahlman, Ferdinand; Walter, Dirk; Curry, Cynthia; Hanley, Allison; Isner, Jeffrey M.; Losordo, Douglas W.

In: Circulation, Vol. 111, No. 16, 26.04.2005, p. 2073-2085.

Research output: Contribution to journalArticle

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T1 - Progressive attenuation of myocardial vascular endothelial growth factor expression is a seminal event in diabetic cardiomyopathy

T2 - Restoration of microvascular homeostasis and recovery of cardiac function in diabetic cardiomyopathy after replenishment of local vascular endothelial growth factor

AU - Yoon, Youngsup

AU - Uchida, Shigeki

AU - Masuo, Osamu

AU - Cejna, Manfred

AU - Park, Jong Seon

AU - Gwon, Hyeon Cheol

AU - Kirchmair, Rudolf

AU - Bahlman, Ferdinand

AU - Walter, Dirk

AU - Curry, Cynthia

AU - Hanley, Allison

AU - Isner, Jeffrey M.

AU - Losordo, Douglas W.

PY - 2005/4/26

Y1 - 2005/4/26

N2 - 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 (phVEGF165). 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 findings suggest that downregulation of VEGF may compromise microvascular homeostasis in the myocardium and thereby play a central role in the pathogenesis of DCM.

AB - 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 (phVEGF165). 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 findings suggest that downregulation of VEGF may compromise microvascular homeostasis in the myocardium and thereby play a central role in the pathogenesis of DCM.

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