Angiotensin II activates MAPK and stimulates growth of human pulmonary artery smooth muscle via AT(1) receptors

To determine a potential role for the renin-angiotensin system in the growt h of human pulmonary artery (PA) smooth muscle, we studied the localization of angiotensin (ANG) II-receptor subtypes by autoradiography in sections o f human PA and in cultured PA smooth muscle. cells (PASMCs) and examined th e growth responses to ANG II in vitro. Specific I-125-labeled [Sar(1),Ile(8 )]ANG II binding was demonstrated within the pulmonary arterial media, but binding to cultured cells varied between isolates; Binding in tissues and c ells was inhibited by the ANG II type 1 (AT(1)) receptor antagonist losarta n but not by the type 2 (AT(2)) receptor antagonist PD-123319. Microautorad iographic studies indicated that cultured PASMCs exhibit heterogeneity with regard to ANG II binding sites. Addition of ANG II to serum-deprived PASMC s, exhibiting a relatively high level of I-125-[Sar(1),Ile(8)]ANG II bindin g, led to a dose-dependent stimulation of DNA synthesis at 24 h and protein synthesis at 48 h. ANG II led to an increase in cell size without an incre ase in cell number. These effects were inhibited by losartan but not by PD- 123319. In addition, ANG II led to rapid activation of mitogen-activated pr otein kinase (MAPK), and ANG II-stimulated DNA synthesis was inhibited by t he specific inhibitor of MAPK PD-98059. We conclude that the AT(1) receptor is expressed by human PASMCs in vivo,and in vitro and is coupled to activa tion of MAPK and increased DNA and protein synthesis in vitro. These result s are consistent with the hypothesis that ANG II may be involved inhuman pu lmonary vascular remodeling.