Effects of Hypoxia on Pulmonary Vascular Smooth Muscle Contraction and Relaxation

The major physiological function of smooth muscle is contraction, which is accomplished by the crossbridge cycling of actin and myosin. The principal mediator of smooth muscle contraction is free intracellular Ca²⁺ which triggers the activity of myosin light chain (MLC) kinase, which then phosphorylates the 20 kD subunit of myosin light chain (MLC₂₀). Contraction velocity is directly proportional to the degree of phosphorylation of MLC₂₀, determined by the balance of activity between MLC kinase and phosphatase. Contractile state is also regulated by the Ca²⁺ sensitivity of the contractile apparatus, mediated by activity of RhoA/Rho-kinase pathway, which increases the degree of MLC₂₀ phosphorylation at a given level of intracellular Ca²⁺. During relaxation, myosin dephosphorylation is stimulated by increased intracellular content and activity of the cyclic nucleotides cGMP and cAMP, which act downstream of nitric oxide- and prostacyclin-mediated signaling, respectively.

Severe and/or prolonged hypoxia leads to sustained pulmonary vasoconstriction and changes in vascular smooth muscle structure and function, which contribute to the pathogenesis of cardiorespiratory disease encountered during early life. In this Chapter, we will discuss the mechanisms by which hypoxia regulates pulmonary vascular smooth muscle contractile state and contributes to pulmonary hypertension, a common condition in the newborn.