ANGIOTENSIN-(1-7) INHIBITS VASCULAR SMOOTH-MUSCLE CELL-GROWTH

Although angiotensin II (Ang II) and the heptapeptide Ang-(1-7) differ by only one amino acid, the two peptides produce different responses in vascular smooth muscle cells. We previously showed that Ang II stim ulated phosphoinositide hydrolysis, whereas Ang II and Ang-(1-7) relea sed prostaglandins. We now report that Ang II and Ang-(1-7) differenti ally modulate rat aortic vascular smooth muscle cell growth. Ang-(1-7) inhibited [H-3]thymidine incorporation in response to stimulation by fetal bovine serum, platelet-derived growth factor, or Ang Ii, The red uction in serum-stimulated thymidine incorporation by Ang-(1-7) depend ed on the concentration of the heptapeptide over the range of 1 nmol/L , to 1 mu mol/L, with a maximal inhibition of 60% by 1 mu mol/L Ang-(1 -7). Ang-(1-7) also inhibited the serum-stimulated increase in cell nu mber to a maximum of 77% by 1 mu mol/L, Ang-(1-7). The attenuation of serum-stimulated thymidine incorporation by Ang-(1-7) was unaffected b y antagonists selective for angiotensin type 1 (ATI) or type 2 (AT(2)) receptors; however, [Sar(1),Ile(8)]Ang II and [Sar(1),Thr(8)]Ang II w ere effective antagonists, indicating that growth inhibition by Ang-(1 -7) was a result of angiotensin receptor activation. In contrast, Ang II stimulated [H-3]thymidine incorporation in cultured vascular smooth muscle cells over the same concentration range, with a maximal stimul ation of 314% at I mu mol/L Ang II. Ang II also increased the total nu mber of cells (to 145% of control), suggesting that enhanced thymidine incorporation was associated with vascular smooth muscle cell prolife ration. The ATI antagonist losartan or L-158,809 but not AT(2) antagon ists blocked [H-3]thymidine incorporation by Ang II. These results sug gest that Ang-(1-7) and Ang Il exhibit opposite effects on the regulat ion of vascular smooth muscle cell growth. The inhibition of prolifera tion by Ang-(1-7) appears to be mediated by a novel angiotensin recept or that is not inhibited by AT(1) or AT(2) receptor antagonists.