Angiotensin-(1-7) Inhibits Vascular Smooth Muscle Cell Growth

Abstract

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 stimulated phosphoinositide hydrolysis, whereas Ang II and Ang-(1-7) released prostaglandins. We now report that Ang II and Ang-(1-7) differentially modulate rat aortic vascular smooth muscle cell growth. Ang-(1-7) inhibited [3H]thymidine incorporation in response to stimulation by fetal bovine serum, platelet-derived growth factor, or Ang II. The reduction in serum-stimulated thymidine incorporation by Ang-(1-7) depended on the concentration of the heptapeptide over the range of 1 nmol/L to 1 mumol/L, with a maximal inhibition of 60% by 1 mumol/L Ang-(1-7). Ang-(1-7) also inhibited the serum-stimulated increase in cell number to a maximum of 77% by 1 mumol/L Ang-(1-7). The attenuation of serum-stimulated thymidine incorporation by Ang-(1-7) was unaffected by antagonists selective for angiotensin type 1 (AT1) or type 2 (AT2) receptors; however, [Sar1,Ile1]Ang II and [Sar1,Thr2]Ang II were effective antagonists, indicating that growth inhibition by Ang-(1-7) was a result of angiotensin receptor activation. In contrast, Ang II stimulated [3H]thymidine incorporation in cultured vascular smooth muscle cells over the same concentration range, with a maximal stimulation of 314% at 1 mumol/L Ang II. Ang II also increased the total number of cells (to 145% of control), suggesting that enhanced thymidine incorporation was associated with vascular smooth muscle cell proliferation. The AT1 antagonist losartan or L-158,809 but not AT2 antagonists blocked [3H]thymidine incorporation by Ang II. These results suggest that Ang-(1-7) and Ang II exhibit opposite effects on the regulation of vascular smooth muscle cell growth. The inhibition of proliferation by Ang-(1-7) appears to be mediated by a novel angiotensin receptor that is not inhibited by AT1 or AT2 receptor antagonists.

Angiotensin‐(1‐7): Pharmacology and New Perspectives in Cardiovascular Treatments

“…Activation of the mas receptor triggers the stimulation of the G-protein, G αq , which results in release of nitric oxide (NO) from the vascular endothelium to mediate vasodilation. Ang-(1-7) administration also decreased the thymidine incorporation in vascular smooth muscle cells (Freeman et al 1996;Tallant and Clark 2003), resulting in a reduction in cellular proliferation and growth. This mechanism was likely due to the receptor's ability to release prostaglandins.…”

Renal actions of angiotensin-(1-7)

“…There is growing evidence that the actions of Ang-(1-7) in the kidney or other sites are mediated by specific receptors (3,10,11,17,22,45,52,53). In the kidney the antidiuretic action of Ang-(1-7) in water-loaded rats is blocked by the selective Ang- (1-7) antagonist A-779 which shows very low affinity for classical angiotensin II receptors (AT 1 and AT 2 subtypes) (22).…”

The Kallikrein-Kinin System as a Regulator of Cardiovascular and Renal Function

“…Moreover, interaction of AT 1 and B 2 potentiates the pressor effect of Ang II (7). On the other hand, interaction of Ang (1-7) with bradykinin has emerged as an endogenous antihypertensive/antitrophic mechanism, opposing many of the effects of Ang II that are mediated by AT1 (80,81,83). Ang (1-7) acting via its receptor Mas (different from AT 1 or AT 2 ) induced bradykinin-mediated hypotension in SHR and normal rats (93) as well as dilatation of porcine coronary arteries (4,31).…”