Fig. 3

The L-arginine-NO biosynthetic pathway regulates key vasculogenic and angiogenic factors in endothelial cells and vascular smooth muscle cells in the placenta. Arginine stimulates placental NO synthesis mainly by enhancing the generation of BH₄, an essential cofactor for NOSs. Estrogen and progesterone augmented the constitutive and inducible NOS activities and the BH₄ concentration in the porcine placenta, thus playing synergetic roles in promoting the placental NO synthesis. The porcine placenta lacks arginase and arginine decarboxylase and thus cannot synthesize ornithine from arginine. NO interacts with critical mediators of angiogenesis (VEGF, PIGF, and the angiopoietins). The induction of angiogenesis by angiopoietin and VEGF proteins is dependent on the amount of VEGF and Ang-1/Ang-2 in endothelial cells. Besides, NO diffuses to the underlying VSMCs where they act on GTP to produce cGMP via guanylate cyclase, which is capable of dilating blood vessels. Ang-1/Ang-2, angiopoietin-1 and angiopoietin-2; BH₄, tetrahydrobiopterin; cGMP, cyclic guanosine monophosphate; eNOS, endothelia nitric oxide synthase; Flt-1, fms-like tyrosine kinase-1; GTP, guanosine; mTOR, mechanistic target of rapamycin; NADP⁺, nicotinamide adenine dinucleotide phosphate; NADPH, nicotinamide adenine dinucleotide phosphate hydrogen; NO, nitric oxide; NOS, nitric oxide synthase; PIGF, placental growth factor; ROS, reactive oxygen species; Tie-2, tunica interna endothelia cell kinase 2; VEGF, vascular endothelial growth factor; VSMCs, vascular smooth muscle cells