Abstract 13170: Microvascular Notch Signaling is Upregulated in Response to Vascular Engothelial Growth Factor and Chronic Myocardial Ischemia
Introduction: Notch signaling is a highly conserved pathway that promotes various types of proliferation including vascular and myocardial growth and development. Ongoing research suggests the VEGF and Notch pathways are tightly linked.We assessed the hypothesis that exogenous VEGF administration to ischemic myocardium would enhance the neovascular response and upregulate Notch signaling.
Methods: Fourteen male Yorkshire swine underwent placement of an ameroid constrictor on the left circumflex artery to induce chronic myocardial ischemia. After 3 weeks, a perivascular pump delivering VEGF to the ischemic area was placed in 7 animals. All animals were examined 7 weeks after ameroid placement. The normal ventricle of the non-pump animals served as the control (NV, n=7), while the two experimental groups were comprised of the area at risk of the non-pump animals (AAR, n=7) and the area at risk of animals treated with perivascular VEGF (VEGF, n=7). Tissues were assessed by Western blot for protein expression and by immunofluorescence for vessel densities, and location of Notch-associated proteins.
Results: Expression of Notch receptors 1, 2, and 3 and Notch ligands Jagged 1 and 2 was significantly higher in the VEGF group as compared to the NV. Capillary and arteriolar density was significantly increased in the VEGF group as compared to NV and AAR. Expression of Angiopoietin-1, p-VE-Cadherin, and TGF-β was higher in the VEGF group compared to NV. Both Jagged 1 and Notch 3 were most highly concentrated in the smooth muscle wall of arterioles.
Conclusions: VEGF administration in the setting of chronically ischemic myocardium not only significantly augmented the neovascular response by an increase in both capillary and arteriolar density, but resulted in an upregulation of several Notch receptors and ligands which were not upregulated with ischemia alone. These findings suggest that Notch signaling plays an integral role in the VEGF-induced neovascular response.
- Cardiovascular therapeutics
- Coronary microcirculation
- Ischemic heart disease
- Myocardial revascularization
- © 2012 by American Heart Association, Inc.