Pulmonary hypertension is characterized by vascular remodeling involving smooth muscle cell proliferation and migration. Calcitonin gene-related peptide (CGRP) and nitric oxide (NO) are potent vasodilators and the inhibition of aortic smooth muscle cell (ASMC) proliferation by NO has been documented, but less is known about the effects of CGRP. The mechanism by which overexpression of CGRP inhibits proliferation in pulmonary artery (PASMC) and ASMC following in vitro transfection by the gene encoding for prepro-CGRP was investigated. Increased expression of p53 is known to stimulate p21 which inhibits G1 Cyclin/cdk complexes thereby inhibiting cell proliferation. We hypothesize that p53 and p21 are involved in the growth inhibitory effect of CGRP. In this study CGRP was shown to inhibit ASMC and PASMC proliferation. In PASMCs transfected with CGRP and exposed to a PKA inhibitor (PKAi) cell proliferation was restored. p53 and p21 expression increased in CGRP treated cells but decreased in cells treated with CGRP and PKAi. PASMCs treated with CGRP and a PKG inhibitor (PKGi) recovered from inhibition of proliferation induced by CGRP. ASMC treated with CGRP and then PKAi or PKGi recovered only when exposed to the PKAi and not PKGi. While CGRP is thought to act through a cAMPdependent pathway, cGMP-involvement in the response to CGRP has been reported. It is concluded that p53 plays a role in CGRP-induced inhibition of cell proliferation and cAMP/PKA appears to mediate this effect in ASMCs and PASMCs whereas cGMP appears to be involved in PASMC proliferation.