No abstract

In this review the factors involved in angiogenesis are discussed in their various roles in initiating angiogenesis and inducing changes in the extracellular matrix to facilitate sprouting angiogenesis which is a major part of the angiogenesis seen in exercise and exercise training. A key role in angiogenesis is played by vascular endothelial growth factor (VEGF). The regulation of blood vessel growth to match the needs of the tissue depends on the control of VEGF production through changes in the stability of its mRNA and in its rate of transcription. The detailed studies describing its characteristics and its upregulation in acute exercise are presented along with a brief overview of the changes in the extracellular matrix that facilitate sprouting angiogenesis that occurs in response to exercise and training. Although the mechanisms involved in the growth and remodeling of arterioles and larger vessels are less detailed some recent studies have provided new insights. These are presented here to show a relationship between capillary development and arteriolar growth or remodeling in exercise training that raises questions to be addressed in future studies.

Exercise training induces coronary vascular adaptations. The goal of this study was to contrast the effects of training on capillary and arteriolar growth. Minipigs were trained for 1, 3, 8, and 16 wk and compared with controls. Maximal O2 consumption increased continuously throughout the study. Capillary and arteriolar densities and diameters, and proliferation of vascular cells in these vessels, were determined in perfusion-fixed tissue. The arterioles were subdivided into five groups according to diameter: 10-19.9, 20-30, 31-40, 41-70, and 71-120 microgram. The total vascular bed cross-sectional area increased by 37% at 16 wk, mainly because of an increase in the number of the small arterioles and an increase in the diameter of the larger vessels. Capillary density increased at 3 wk and then returned to control levels by 16 wk; concomitantly, the number of arterioles (20-30 microgram) increased at 16 wk. We speculate that the "extra" capillaries observed at 3 wk were the source of the new arterioles.

We have quantified the development of the coronary collateral circulation in the pig. The collateral circulation was induced to grow by placing an ameroid occluder on the left circumflex coronary artery. Two to 16 weeks after ameroid placement, the coronary collateral circulation was identified after the injection of several colors of a silicone polymer into the coronary arteries and the aorta. We identified intercoronary and extracardiac collaterals and quantified their number, location, size, and wall thickness. Intercoronary collaterals grew to a level that represents a 14-fold increase in normal collateral blood flow under resting conditions compared with the values in an animal not subjected to coronary artery occlusion. Extracardiac collaterals could potentially supply approximately 30% of resting flow. The sources of the extracardiac collaterals were the bronchial and internal mammary arteries. Coronary collateral morphometry and DNA synthesis in the pig heart also were examined. Coronary collaterals had significantly less smooth muscle than did normal arterioles. This may account, in part, for the reduced response of the coronary collaterals to vasodilators. We observed intense DNA synthesis in endothelial and smooth muscle cells in the first 2 or 3 weeks of ischemia. However, DNA synthesis rapidly ceased after this time, coincident with coronary collateral reserve values (ischemic/nonischemic regional blood flow ratios during maximal vasodilation) reaching their maximum level. This suggests that failure of the vessels to continue proliferating accounts for the occurrence of the plateau in blood flow levels.

Coronary collateral development was examined in 34 pigs after gradual occlusion of the left circumflex coronary artery (LCX) with an Ameroid constrictor. Collateral development was assessed by measurements of myocardial blood flow and regional myocardial function at rest and during exercise over a 16-wk period after placement of the constrictor. Coronary collateral development was adequate to prevent severe infarction and restore blood flow to the collateral-dependent LCX region within 3-7 wk. Infarction averaged 5.0 +/- 1.3% of the LCX region. Blood flows at rest were 1.05 +/- 0.14 and 1.13 +/- 0.15 ml.min-1.g-1 in the subendocardium of the collateral and control regions, respectively, 7 wk postoperatively. Concurrently, collateral vessel development supported normal myocardial function at rest as determined by systolic wall thickening in the LCX region. However, collateral development was limited, since blood flows during moderate and severe exercise were reduced in the LCX region compared with control and left anterior descending and right coronary regions. Blood flow ratios (collateral/control flow) during severe exercise 3 wk postoperatively were 0.23 +/- 0.03 and 0.57 +/- 0.05 in the subendocardium and subepicardium and were constant throughout the 16-wk period throughout the study. Myocardial function of the collateral region also was reduced during exercise and a 30-min recovery period. We suggest that this limited coronary collateral circulation, which develops in response to gradual coronary occlusion in swine, serves as a model for the human collateral circulation for the study of protocols to alter growth and development of coronary collateral vessels.