Hypoxic Regulation of Vascular Proteasomal Degradation of MLCK

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Chronic exposure of in‐utero fetuses to severe hypoxia induces maladaptive changes in vascular structure and function, and elevates postnatal susceptibility to metabolic, endocrine, cardiovascular diseases. Correspondingly, multiple studies have demonstrated that chronic hypoxia depresses vascular contractility through mechanisms that remain to be fully elucidated. Our recent studies have shown that in fetal arteries chronic hypoxia decreases the abundance and activity of myosin light chain kinase, which is the rate‐limiting enzyme for force generation in smooth muscle cells. Here we hypothesize that chronic hypoxia decreases vascular contractility via age dependent increases in proteasomal degradation of MLCK protein. To test this hypothesis we used a well established chronic hypoxia model involving pregnant ewes maintained at sea level or at altitude (3280m) during the last 110 days of gestation. In vitro contractility experiments revealed that chronic hypoxia decreased maximum myogenic stress by 56%. Chronic hypoxia also significantly decreased MLCK abundance, and moreso in fetal (90%) than adult (47%) arteries. Conversely, qPCR measurements of MLCK mRNA revealed similar abundances in adult and fetal arteries, suggesting that increased loss of MLCK was not due to inhibition of transcription. To more directly elucidate mechanisms of MLCK degradation, the effects of MG132 (a potent inhibitor of proteasomal degradation) were quantified organ cultured fetal and adult arteries. Rates of MLCK degradation averaged 0.83 ± 0.21 in fetal and 0.99 ± 0.38 in adult normoxic arteries. With chronic hypoxia, degradation rates increased by 53% and 61% in fetal and adult arteries respectively. Together these data suggest that depressed contractile activity during hypoxic acclimatization occurs via hypoxic promotion of proteasomal degradation of MLCK slightly more in adult than fetal arteries. Support or Funding Information These studies were supported by an NIH Program Project grant from NICHD (HD31266,) and an NIH R01 grant from NINDS (NS076945).

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