1. Introduction

Fig. 1. Vascular growth in response to cardiac hypertrophy may include: (1) angiogenesis, i.e. growth of capillaries by sprouting or intussusception (partitioning to bifurcate a capillary), and (2) arteriogenesis, i.e. creation of a new arteriole via recruitment of smooth muscle cells to an endothelial tube, or remodeling of an existing arteriole or artery to increase its diameter.

setting. In humans, long-term pressure overload-induced hypertrophy is associated with a decrease in coronary reserve, which has generally been attributed to an absence or inadequate growth of the coronary vasculature. Many experimental studies on animal models with various forms of pressure overload have also concluded that angiogenesis, if it occurs, does not compensate for the increase in ventricular mass (reviewed in Refs. 2 and 3). A decline in coronary reserve and/or maximal myocardial perfusion has also been documented in a variety of animal species, e.g. rat, cat, pig and dog.4−10 However, hypertension, as well as cardiac hypertrophy, contribute to the decline in coronary reserve.11 Work from our lab showed that cardiac hypertrophy and arterial pressure could be dissociated.12,13 Normalization of blood pressure with hydralazine in spontaneously hypertensive rats markedly reduced minimal coronary

256 R. J. Tomanek & E. I. Dedkov

vascular resistance and normalized coronary reserve, despite the persistence of cardiac hypertrophy.13 Subsequently, we explored the effect of reversing established cardiac hypertrophy and elevated blood pressure on maximal myocardial perfusion.14 ACE inhibition normalized arterial pressure and minimal coronary vascular resistance, even though it did not totally regress left ventricular hypertrophy. Thus, impairment of flow in pressure overload hypertrophy is due, in part, to the chronic hypertension-altered vessel reactivity, e.g. impaired dilation.11

Proliferation of endothelial cells in the myocardium of rats with either aortic constriction or renal hypertension was absent as shown by [3H] thymidine labeling.15. Inadequate capillary growth results in increased diffusion distances and capillary domains, i.e. the tissue served by a capillary.2,16 In contrast, several studies have shown that right or left ventricular hypertrophy in response to pressure overload can be associated with proportional vascular growth of the coronary vasculature (Table 1). In spontaneously hypertensive rats, stabilization of myocardial hypertrophy permits capillary growth to compensate for the additional cardiac mass.17,18 Moreover, coronary reserve and minimal coronary vascular resistance normalize over time.5,19 The angiogenesis associated with stabilized hypertrophy correlates with an elevation in VEGF mRNA which has been shown to occur at 28 and 32 weeks of age in SHR.20 Dogs with renal hypertension (one kidney, one clip) of six weeks duration were found to have moderate (27%) left ventricular hypertrophy and a 67% increase in minimal coronary vascular resistance.10 However, when the renal hypertension was prolonged to seven months, dogs exhibited normal LV-MCVR, arteriolar numeral densities, despite the fact that LV weight was higher than controls.21

Right ventricular hypertrophy evoked by pulmonary artery banding in dogs,22 and swine23,24 was associated with normal or decreased MCVR. Arteriogenesis, as indicated by arteriolar densities that were similar to the controls, occurred in a model of progressive pulmonary artery constriction that caused a 91% increase in RV weight.24 Capillary density, however, was lower in the pressure overload group, a finding that supports the concept that growth of capillaries and arterioles is not necessarily parallel. In sum, there are many reports in the literature that

Table 1. Angiogenesis and arteriogenesis in pressure overload cardiac hypertrophy.

LV = Left ventricle; RV = right ventricle; P.A. = pulmonary artery; MCVR = minimal coronary vascular resistance; 1K = one kidney; 1C = one clip; SHR = spontaneously hypertensive rat.