Effects of certain vasoactive peptides on pathogenesis of vascular restenosis.
OBJECTIVE
To investigate the effects of several vasoactive peptides on the development of arterial restenosis after balloon angioplasty.


METHODS
In rat aortic artery restenosis model produced by denudation of aortic endothelia, we observed changes of endothelin (ET), angiotensin II (AII), calcitonin gene-related peptide (CGRP) and adrenomedullin (Adm) in plasma and aorta with radioimmunoassay and expression of hypertension-related gene (HRG-1) with semi-quantitative RT-PCR, and studied the effects of these peptides on intimal hyperplasia, intima/media ratio and MAPK activities of aortic artery after angioplasty respectively. Furthermore, in cultured cells, we studied the effects of these peptides on vascular smooth muscle cell (VSMC) proliferation and expression of HRG-1 of VSMC from spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats with 3H-TdR incorporation and RT-PCR respectively.


RESULTS
After angioplasty, the levels of ET and AII in plasma and aorta significantly increased, accompanied with VSMC proliferation and neointima hyperplasia. On day 10 after angioplasty, the levels of ET in plasma and aorta increased by 69% and 124% respectively, compared with sham group (P < 0.01); and the level of aortic AII increased by 80% (P < 0.01). Antiserum against ET or inhibitors of angiotensin converting enzyme (ACE) could significantly inhibit the proliferation of VSMC and neointima formation. Compared with the sham group, on day 3 after angioplasty, the CGRP levels in plasma and aorta increased by 64% and 89% respectively (P < 0.01) and the Adm levels in plasma and tissue increased by 129% and 102% respectively (P < 0.01). On day 10, intravenous administration of CGRP significantly inhibited the proliferation of VSMC and neointima formation induced by balloon aortic injury (by 66% and 79% respectively, P < 0.01). In addition, ET and AII attenuated the expression of HRG-1 in aorta and stimulated mitogen-activated protein kinase (MAPK) activity, while CGRP and Adm potentiated the expression of HRG-1 and inhibited MAPK.


CONCLUSIONS
ET and AII can stimulate the proliferation of injured intima while CGRP and Adm have an anti-hyperplasia effect after angioplasty. These 4 peptides are involved in the regulation of VSMC proliferation and affect the development of vascular restenosis by regulating the expression of HRG-1 and MAPK activity.
Liu
Naikui
N
Institute of Cardiovascular Research, the First Hospital, Peking University, Beijing 100034.
Chen
Guanghui
G
Wang
Xiaohong
X
Yao
Xinghai
X
Su
Jialin
J
Li
Tianchang
T
Wu
Xudong
X
Zhang
Yonggang
Y
Tang
Jian
J
Tang
Chaoshu
C
D053607:Adrenomedullin; D000800:Angioplasty, Balloon / Q000009:adverse effects; D000804:Angiotensin II / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001013:Aorta, Thoracic / Q000166:cytology / Q000378:metabolism; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology / Q000627:therapeutic use; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D023903:Coronary Restenosis / Q000209:etiology* / Q000378:metabolism; D019332:Endothelin-1 / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D010455:Peptides / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D017208:Rats, Wistar; D014665:Vasodilator Agents / Q000494:pharmacology* / Q000627:therapeutic use
D019332:Endothelin-1; D010455:Peptides; D014665:Vasodilator Agents; D000804:Angiotensin II; D053607:Adrenomedullin; D020928:Mitogen-Activated Protein Kinases; D015740:Calcitonin Gene-Related Peptide