The proliferative response to vascular injury is suppressed by angiotensin-converting enzyme inhibition

Jerry S Powell, R. K M Muller, M. Rouge, H. Kuhn, F. Hefti, H. R. Baumgartner

Research output: Contribution to journalArticle

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Abstract

Smooth muscle cell (SMC) proliferation and formation of extracellular matrix in the intima of muscular arteries are major processes that can lead to vascular stenosis in arteriosclerosis or after coronary angioplasty. These processes are also seen in the proliferative response to balloon catheter-induced vascular injury of the rat carotid artery, and result in marked neointima formation by 14 days after catheterization. We have shown recently that the angiotensin-converting enzyme (ACE) inhibitor cilazapril strongly suppressed this development of neointima. In this report, we show that the beneficial effects on neointima formation persist for at least 8 weeks after stopping treatment with cilazapril, and that continuous treatment may have additional inhibitory effects during the late phases of vascular remodeling after injury. To investigate further the possible mechanisms, we examined several vasoactive compounds in this model. Another ACE inhibitor of a different chemical class, captopril, reduced neointima formation as strongly as cilazapril (67 and 78%, respectively), but the calcium antagonist verapamil was not active as an inhibitor of neointima formation, despite similar lowering of blood pressure. Hydralazine and a new calcium antagonist, Ro 40-5967, partially suppressed neointima formation (36%, p < 0.005 and 33%, p < 0.05, respectively). In vitro, neither cilazapril nor its active metabolite, cilazaprilate, had any effect on SMC proliferation in response to serum or PDGF. To characterize further the role of angiotensin II (Ang II), we tested in cell culture the effects of Ang II and cilazaprilate on mRNA levels of several proteins potentially involved in regulating the SMC response. Cilazaprilate did not alter the Ang II-induced increases of c-fos, c-myc, PDGF-A, and TGF-β, or the Ang II-induced decrease of PDGF α receptor mRNAs. These results indicate that the converting enzyme has an important role in the proliferative response to vascular injury, and suggest that Ang II may be a critical regulatory factor in vivo during the response.

Original languageEnglish (US)
JournalJournal of Cardiovascular Pharmacology
Volume16
Issue numberSUPPL. 4
StatePublished - 1990
Externally publishedYes

Fingerprint

Neointima
Vascular System Injuries
Peptidyl-Dipeptidase A
Cilazapril
Angiotensin II
Smooth Muscle Myocytes
Angiotensin-Converting Enzyme Inhibitors
Mibefradil
Cell Proliferation
Calcium
Platelet-Derived Growth Factor Receptors
Hydralazine
Messenger RNA
Arteriosclerosis
Captopril
Verapamil
Angioplasty
Carotid Arteries
Catheterization
Extracellular Matrix

Keywords

  • ACE inhibition
  • Angioplasty
  • Cilazapril
  • Neointima
  • Smooth muscle cell proliferation
  • Vascular injury

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Pharmacology

Cite this

The proliferative response to vascular injury is suppressed by angiotensin-converting enzyme inhibition. / Powell, Jerry S; Muller, R. K M; Rouge, M.; Kuhn, H.; Hefti, F.; Baumgartner, H. R.

In: Journal of Cardiovascular Pharmacology, Vol. 16, No. SUPPL. 4, 1990.

Research output: Contribution to journalArticle

Powell, Jerry S ; Muller, R. K M ; Rouge, M. ; Kuhn, H. ; Hefti, F. ; Baumgartner, H. R. / The proliferative response to vascular injury is suppressed by angiotensin-converting enzyme inhibition. In: Journal of Cardiovascular Pharmacology. 1990 ; Vol. 16, No. SUPPL. 4.
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AU - Hefti, F.

AU - Baumgartner, H. R.

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AB - Smooth muscle cell (SMC) proliferation and formation of extracellular matrix in the intima of muscular arteries are major processes that can lead to vascular stenosis in arteriosclerosis or after coronary angioplasty. These processes are also seen in the proliferative response to balloon catheter-induced vascular injury of the rat carotid artery, and result in marked neointima formation by 14 days after catheterization. We have shown recently that the angiotensin-converting enzyme (ACE) inhibitor cilazapril strongly suppressed this development of neointima. In this report, we show that the beneficial effects on neointima formation persist for at least 8 weeks after stopping treatment with cilazapril, and that continuous treatment may have additional inhibitory effects during the late phases of vascular remodeling after injury. To investigate further the possible mechanisms, we examined several vasoactive compounds in this model. Another ACE inhibitor of a different chemical class, captopril, reduced neointima formation as strongly as cilazapril (67 and 78%, respectively), but the calcium antagonist verapamil was not active as an inhibitor of neointima formation, despite similar lowering of blood pressure. Hydralazine and a new calcium antagonist, Ro 40-5967, partially suppressed neointima formation (36%, p < 0.005 and 33%, p < 0.05, respectively). In vitro, neither cilazapril nor its active metabolite, cilazaprilate, had any effect on SMC proliferation in response to serum or PDGF. To characterize further the role of angiotensin II (Ang II), we tested in cell culture the effects of Ang II and cilazaprilate on mRNA levels of several proteins potentially involved in regulating the SMC response. Cilazaprilate did not alter the Ang II-induced increases of c-fos, c-myc, PDGF-A, and TGF-β, or the Ang II-induced decrease of PDGF α receptor mRNAs. These results indicate that the converting enzyme has an important role in the proliferative response to vascular injury, and suggest that Ang II may be a critical regulatory factor in vivo during the response.

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