Faculty Collaboration Database

Ischemia-induced coronary collateral growth is dependent on vascular endothelial growth factor and nitric oxide. Circulation 2000 Dec 19;102(25):3098-103

Date

01/11/2000

Pubmed ID

11120701

DOI

10.1161/01.cir.102.25.3098

Scopus ID

2-s2.0-0034687598 (requires institutional sign-in at Scopus site)   200 Citations

Abstract

BACKGROUND: We hypothesized that ischemia-induced expression of vascular endothelial growth factor (VEGF) and the production of NO stimulate coronary collateral growth.

METHODS AND RESULTS: To test this hypothesis, we measured coronary collateral blood flow and VEGF expression in myocardial interstitial fluid in a canine model of repetitive myocardial ischemia under control conditions and during antagonism of NO synthase. Collateralization was induced by multiple (1/h; 8/d), brief (2 minutes) occlusions of the left anterior descending coronary artery for 21 days. In controls, collateral blood flow (microspheres) progressively increased to 89+/-9 mL. min(-1). 100 g(-1) on day 21, which was equivalent to perfusion in the normal zone. Reactive hyperemic responses (a measure of the severity of ischemia) decreased as collateral blood flow increased. In N(G)-nitro-L-arginine methyl ester (L-NAME)- and L-NAME+nifedipine-treated dogs, to block the production of NO and control hypertension, respectively, collateral blood flow did not increase and reactive hyperemia was robust throughout the occlusion protocol (P<0.01 versus control). VEGF expression (Western analyses of VEGF(164) in myocardial interstitial fluid) in controls peaked at day 3 of the repetitive occlusions but waned thereafter. In sham-operated dogs (instrumentation but no occlusions), expression of VEGF was low during the entire protocol. In contrast, VEGF expression was elevated throughout the 21 days of repetitive occlusions after L-NAME. Reverse transcriptase-polymerase chain reaction analyses revealed that the predominant splice variant expressed was VEGF(164).

CONCLUSIONS: NO is an important regulator of coronary collateral growth, and the expression of VEGF is induced by ischemia. Furthermore, the induction of coronary collateralization by VEGF appears to require the production of NO.

Author List

Matsunaga T, Warltier DC, Weihrauch DW, Moniz M, Tessmer J, 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
Arterial Occlusive Diseases
Blotting, Western
Collateral Circulation
Coronary Vessels
Dogs
Endothelial Growth Factors
Enzyme Inhibitors
Female
Hemodynamics
Hyperemia
Lymphokines
Male
Myocardial Ischemia
NG-Nitroarginine Methyl Ester
Nitric Oxide
Nitric Oxide Synthase
RNA, Messenger
Reverse Transcriptase Polymerase Chain Reaction
Vascular Endothelial Growth Factor A
Vascular Endothelial Growth Factors