Figure 1.

Pulmonary vasoconstriction is orchestrated. Neural, hormonal, and humoral mediators, as well as tissue hypoxia, constrict the lung vasculature in utero and maintain a high level of fetal pulmonary vascular resistance. Many of these agonists work through a G_q-coupled receptor pathway to activate a number of intracellular signaling systems that lead to pulmonary vascular smooth muscle cell contraction. These pathways are detailed in the text and ultimately cause simultaneous activation of myosin light-chain kinase (MLCK) and inhibition of myosin light-chain phosphatase (MLCP). The mechanisms associated with hypoxia-induced pulmonary vasoconstriction are controversial but overlap those of the other mediators. Adult animal studies illustrate that the hypoxia-induced pulmonary vasoconstriction response includes a combination of activation of L-type Ca²⁺ channels (Ca_L), ryanodine receptors (RyRs), Rho-kinase, nonselective cation channels, and inhibition of K⁺ channels. A dashed green arrow indicates an activation pathway; a dashed red line with a bar indicates an inhibition pathway; a dashed blue arrow indicates movement of calcium. CaM/CAMKII: calmodulin and Ca²⁺/calmodulin-dependent protein kinase II; Cl_Ca: calcium-activated chloride channel; CPI-17: C-kinase potentiated protein phosphatase-1 inhibitor; DAG: diacylglycerol; Em: membrane potential; ET-1: endothelin-1; G_q: q alpha subunit of G protein–coupled receptor; InsP₃/InsP₃R: inositol 1,4,5 triphosphate and associated receptor; K_v: voltage-dependent potassium channel; MLC₂₀/MLC_20-P: 20-kDa myosin light chain and phosphorylated moiety; NE: norepinephrine; NSCC: nonselective cation channel; PAF: platelet-activating factor; PGF_2α: prostaglandin F_2α; PKC: protein kinase C; PLC: phospholipase C; PP1c: protein phosphatase-1c; RhoA/ROCK: Ras homolog gene family, member A, and associated kinase; SERCA: sarco/endoplasmic reticulum Ca²⁺-ATPase; 5-HT: serotonin.