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Vascular endothelial growth factor is required for coronary collateral growth in the rat
Eiji Toyota1, David C Warltier, Tommy Brock
1Department of Physiology, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA.
Insights
Vascular endothelial growth factor (VEGF) is critical for coronary collateral growth. Blocking VEGF in rats prevented the development of new blood vessels after repeated ischemia, confirming its essential role.
Area of Science:
- Cardiovascular Biology
- Angiogenesis Research
- Ischemic Heart Disease Models
Background:
- Coronary collateral growth is associated with vascular endothelial growth factor (VEGF).
- Previous studies suggested a link but did not establish a causal role for VEGF in collateral development.
- Understanding VEGF's role is crucial for therapeutic strategies targeting coronary artery disease.
Purpose of the Study:
- To determine if vascular endothelial growth factor (VEGF) expression is essential for coronary collateral growth.
- To investigate the causal relationship between VEGF and the development of new blood vessels in the heart.
Main Methods:
- Repetitive myocardial ischemia (RI) was induced in rats over 10 days.
- Collateral growth was assessed by measuring blood flow with radioactive microspheres.
- Arterial-arterial anastomoses were visualized using x-ray micro-CT.
- Animals were divided into sham, RI, and RI with anti-VEGF treatment groups.
Main Results:
- Repetitive ischemia (RI) increased collateral blood flow approximately six-fold.
- Treatment with anti-VEGF completely blocked the increase in collateral blood flow and the formation of new arterial-arterial anastomoses.
- Collateral growth in the RI group was functional, preserving cardiac function during occlusion, unlike in the anti-VEGF group.
Conclusions:
- Vascular endothelial growth factor (VEGF) expression is critical for the growth of coronary collaterals.
- VEGF plays a causal role in the development of functional coronary collateral circulation.
- Targeting VEGF may be a viable strategy to promote collateral growth in ischemic heart disease.
Background:
The goal of this study was to determine whether the expression of vascular endothelial growth factor (VEGF) is critical for coronary collateral growth. Previous studies have provided an association between coronary collateral growth and VEGF, but none have allowed determination of a causal role.
Methods And Results:
We measured coronary collateral growth in rats subjected to repetitive episodes of myocardial ischemia (RI; one 40-second occlusion every 20 minutes for 2 hours 40 minutes, followed by 5 hours 20 minutes of rest, with this 8-hour cycle repeated 3 times per day for 10 days). Collateral growth was measured from blood flow (radioactive microspheres), visualization of arterial-arterial anastomoses (x-ray micro-CT), and maintenance of function during complete coronary occlusion in 3 groups of animals: sham (received instrumentation but no RI), experimental (subjected to RI), and anti-vascular endothelial growth factor (RI+anti-VEGF 0.6 mg/100 g per day) to block the endogenous actions of VEGF. In the 3 groups, native collateral flow (measurement for RI or sham protocol) averaged 0.2 to 0.3 mL x min(-1) x g(-1) of tissue. In the sham group, collateral flow did not increase during the protocol. Collateral flow in the control RI group increased by approximately 6-fold to 1.63 mL x min(-1) x g(-1) tissue, but in the anti-VEGF group, collateral flow did not increase after the RI protocol (0.22 mL x min(-1) x g(-1)). In acute experiments, collateral flow was unchanged during vasodilation with dipyridamole, indicating the increases in collateral flow are due to collateral growth and not vasodilation. X-ray micro-CT analysis revealed a 3-fold increase (versus sham group) in the number of arterial-arterial anastomoses per heart after RI, which was prevented by treatment with anti-VEGF. The growth of the collateral circulation was functional in the RI group because complete coronary occlusion did not induce any untoward effects on hemodynamics or arrhythmias. In the sham or anti-VEGF groups, coronary occlusion at the end of the protocol induced many arrhythmias and deterioration of function.
Conclusions:
From these results, we conclude that the expression of VEGF is critical to the growth of coronary collaterals.
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