Inhibitors of Angiotensin-Converting Enzyme Prevent Myointimal Proliferation After Vascular Injury

Abstract

The role of a local angiotensin system in the vascular response to arterial injury was investigated by administering the angiotensin-converting enzyme (CE) inhibitor cilazapril to normotensive rats in which the left carotid artery was subjected to endothelial denudation and injury by balloon catheterization. In control animals, by 14 days after balloon injury, the processes of smooth muscle cell (SMC) proliferation, migration of SMCs from the media to the intima, and synthesis of extracellular matrix produced marked thickening of the intima, with reduction of the cross-sectional area of the lumen. However, in animals that received continuous treatment with the CE inhibitor, neointima formation was decreased (by about 80 percent), and lumen integrity was preserved. Thus, the angiotensin-converting enzyme may participate in modulating the proliferative response of the vascular wall after arterial injury, and inhibition of this enzyme may have therapeutic applications to prevent the proliferative lesions that occur after coronary angioplasty and vascular surgery.

Participation of kinins in the captopril‐induced inhibition of intimal hyperplasia caused by interruption of carotid blood flow in the mouse

“…The potential of angiotensin-converting enzyme (ACE) inhibitors in prevention of neointima formation was ®rst addressed in a rat model of carotid artery balloon injury (Powell et al, 1989). This protective e ect was mainly attributed to inhibition of the ACE-induced generation of angiotensin II a potent vasopressor implicated in vascular smooth muscle cell (SMC) growth (Itoh et al, 1993), proliferation (Huckle & Earp, 1994), and migration (Farhy et al, 1997).…”

Effect of an angiotensin II receptor antagonist, candesartan cilexetil, on canine intima hyperplasia after balloon injury

“…Studies have shown that: (1) vascular hypertrophy is reduced by angiotensinconverting enzyme (ACE) inhibitors or Ang II receptor antagonists; [1][2][3][4] (2) components of the reninangiotensin system, such as ACE, 5,6 and angiotensinogen mRNA 7 are activated or increased in the area of vascular hypertrophy; and (3) Ang II promotes migration, proliferation, and hypertrophy of vascular smooth muscle cells, and generation of extracellular matrix, as seen in in vitro and in vivo models. [8][9][10][11] Because intima hyperplasia after balloon injury could be reduced by treatment of ACE inhibitors in rats, 3 ACE inhibitors were expected to be effective in clinical use. However, ACE inhibitors failed to reduce the restenosis seen after clinical PTCA.…”

Aspects of gene polymorphisms in cardiovascular disease: the renin‐angiotensin system

“…The growth-promoting effects of Ang II are modulated, under normal conditions, by endothelium-derived factors. Removal of the endothelium, for example by balloon injury, may alter the vascular structure and promote the development of intimal hyperplasia, and this may be reverted by ACE inhibition in experimental animal models [17,18].…”

“…Increased tissue angiotensin concentrations are probably critical for the neointima development, as shown by the fact that, in several animal species, ACE-inhibitors and AT 1 receptor antagonists can prevent neointimal hyperplasia in response to vascular injury [18,20]. The removal of endothelium, for example after balloon injury, allows angiotensin to exert a direct growth-promoting effect on vascular smooth muscle cells [4].…”

“…Dzau et al have indeed suggested a prominent role of the RAS system in the pathogenesis of restenosis, demonstrating that Ang II can modulate smooth muscle cell growth in vitro [20]. In vivo studies have reported that Ang II infusion induces marked intimal smooth muscle cell proliferation in rat carotid arteries [17,21], and that ACE inhibitors suppress myointimal proliferation after vascular injury [14,18]. Intimal thickening can also be prevented by Ang II receptor type-1 antagonists [66].…”