Faculty Collaboration Database

Expression of VEGF and angiopoietins-1 and -2 during ischemia-induced coronary angiogenesis. Am J Physiol Heart Circ Physiol 2003 Jul;285(1):H352-8

Date

03/22/2003

Pubmed ID

12649074

DOI

10.1152/ajpheart.00621.2002

Scopus ID

2-s2.0-0037662854 (requires institutional sign-in at Scopus site)   91 Citations

Abstract

The mechanisms underlying coronary capillary growth in response to ischemia are undefined. We hypothesized that the expression of vascular endothelial growth factor (VEGF) and angiopoietin (Ang)/Tie-2 were involved in capillary growth as an adaptation to ischemia. To test this hypothesis we measured capillary density, and the expressions of VEGF, Ang-1, Ang-2, and the Tie-2 receptor and its phosphorylation state during repetitive episodes of myocardial ischemia in chronically instrumented canines. Repetitive episodes of ischemia were induced by multiple (once/hour; 8/day), brief (2 min) occlusions of the left anterior descending coronary artery for 1, 7, 14, or 21 days. A sham group received the same instrumentation as the experimental groups but not the occlusion protocol. Collateral blood flow (microspheres) progressively increased from 9 +/- 3 to 83 +/- 10 ml. min-1. 100 g-1 on day 21. Capillary density increased at day 7 from 2378 +/- 53 (sham) to 2962 +/- 60/mm2, but it decreased to 2594 +/- 39/mm2 at day 21. Both VEGF and Ang-2 expression in myocardial interstitial fluid (Western analyses) peaked at day 3 of the repetitive occlusions but waned thereafter. In contrast the expression of Ang-1 remained relatively constant at all times in the occlusion groups. In shams, the expression of VEGF and Ang-2 was low and constant at all times. Tie-2 phosphorylation myocardial decreased decreased at day 7 but increased at 21 days of occlusions (P < 0.05). Our results indicate that capillary density was augmented by myocardial ischemia, but after development of collaterals and restoration of flow to the ischemic zone, capillary density returned to control levels. The change in capillary density paralleled with VEGF and Ang-2 expression but was inversely related to Tie-2 phosphorylation. We speculate the coronary angiogenesis is a coordinated event involving the expression of both VEGF and Ang-2 and that therapeutic angiogenic strategies may ultimately require treatment with more than a single factor.

Author List

Matsunaga T, Warltier DC, Tessmer J, Weihrauch D, Simons M, Chilian WM

Author

Dorothee Weihrauch DVM, PhD Research Scientist II in the Anesthesiology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Angiogenesis Inducing Agents
Angiopoietin-1
Angiopoietin-2
Animals
Blotting, Western
Capillaries
Collateral Circulation
Coronary Circulation
Dogs
Endothelial Growth Factors
Extracellular Space
Female
Heart Rate
Intercellular Signaling Peptides and Proteins
Lymphokines
Male
Membrane Glycoproteins
Myocardial Ischemia
Myocardium
Neovascularization, Pathologic
Phosphorylation
RNA, Messenger
Reverse Transcriptase Polymerase Chain Reaction
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factors