Faculty Collaboration Database

Repetitive coronary artery occlusions induce release of growth factors into the myocardial interstitium. Am J Physiol 1998 Sep;275(3):H969-76

Date

09/02/1998

Pubmed ID

9724302

DOI

10.1152/ajpheart.1998.275.3.H969

Scopus ID

2-s2.0-0031678622 (requires institutional sign-in at Scopus site)   39 Citations

Abstract

Our objective was to delineate the temporal sequence of mitogenic activity in myocardial interstitial fluid (IF) during enhancement of collateral growth. Collateral development in chronically instrumented dogs was induced by eight 2-min coronary occlusions/day for 21 days. Collateralization was assessed by measurement of blood flow in the region distal to a total coronary occlusion. Myocardial IF was obtained periodically from an intramyocardial catheter, and mitogenic activity was assessed by proliferative response of cultured endothelial cells (EC) and vascular smooth muscle cells (VSMC) to the IF. Three experiments were conducted to test that the mitogenic activity is induced by protein growth factors: 1) protein digestion of the myocardial IF with Pronase-coupled latex beads; 2) heat inactivation (boiling) of the IF; and 3) neutralization of the mitogenic activity with antibodies for basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF). Blood flow was reconstituted to baseline levels during occlusion after 3 wk of repetitive coronary occlusions. After initiation of occlusion the mitogenic activity of the myocardial IF on VSMC and EC increased up to days 12-14 and was reduced on days 19-23. Pronase treatment and heat inactivation blocked the mitogenic effect. Treatment with antibodies for bFGF and VEGF neutralized the proliferative response to the myocardial IF at specific times. bFGF antibody inhibited the mitogenic effect significantly on days 12-14. VEGF antibody neutralized the mitogenicity of the myocardial IF on day 7, days 12 and 13, and days 19 and 20 significantly. We conclude that myocardial IF harvested from ischemic myocardium is highly mitogenic up to 2 wk after initiation of repetitive coronary occlusions. After 3 wk of ischemia, the degree of mitogenic activity for VSMC and EC was decreased from peak levels. The antibodies could not neutralize the mitogenic effect of the myocardial IF during this time period. These results suggest that mitogens are expressed during various stages of collateral development in a time-dependent manner, that the mitogens are proteinaceous in nature, and that bFGF and VEGF are released into the myocardial IF.

Author List

Weihrauch D, Tessmer J, Warltier DC, 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

Animals
Antibodies
Cell Division
Cells, Cultured
Constriction
Coronary Disease
Coronary Vessels
Dogs
Endothelial Growth Factors
Endothelium, Vascular
Extracellular Space
Female
Fibroblast Growth Factor 2
Growth Substances
Hot Temperature
Lymphokines
Male
Muscle, Smooth, Vascular
Pronase
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factors