Chronic hypoxia alters fetal cerebrovascular responses to endothelin-1

Abstract

In utero hypoxia influences the structure and function of most fetal arteries, including those of the developing cerebral circulation. Whereas the signals that initiate this hypoxic remodeling remain uncertain, these appear to be distinct from the mechanisms that maintain the remodeled vascular state. The present study explores the hypothesis that chronic hypoxia elicits sustained changes in fetal cerebrovascular reactivity to endothelin-1 (ET-1), a potent vascular contractant and mitogen. In fetal lambs, chronic hypoxia (3,820-m altitude for the last 110 days of gestation) had no significant effect on plasma ET-1 levels or ETA receptor density in cerebral arteries but enhanced contractile responses to ET-1 in an ETA-dependent manner. In organ culture (24 h), 10 nM ET-1 increased medial thicknesses less in hypoxic than in normoxic arteries, and these increases were ablated by inhibition of PKC (chelerythrine) in both normoxic and hypoxic arteries but were attenuated by inhibition of CaMKII (KN93) and p38 (SB203580) in normoxic but not hypoxic arteries. As indicated by Ki-67 immunostaining, ET-1 increased medial thicknesses via hypertrophy. Measurements of colocalization between MLCK and SMαA revealed that organ culture with ET-1 also promoted contractile dedifferentiation in normoxic, but not hypoxic, arteries through mechanisms attenuated by inhibitors of PKC, CaMKII, and p38. These results support the hypothesis that chronic hypoxia elicits sustained changes in fetal cerebrovascular reactivity to ET-1 through pathways dependent upon PKC, CaMKII, and p38 that cause increased ET-1-mediated contractility, decreased ET-1-mediated smooth muscle hypertrophy, and a depressed ability of ET-1 to promote contractile dedifferentiation.

H2S mediates the vasodilator effect of endothelin-1 in the cerebral circulation

“…The vasoconstrictor effect of ET-1 has been implicated in the cerebrovascular dysfunction occurring in stroke, subarachnoid hemorrhage, chronic intermittent hypoxia, and brain trauma (1,5,9,11,18,23,26,27,31). It is generally accepted that the mechanisms of vasoconstrictor effects of ET-1 involves smooth muscle ET A receptors that initiate phosphorylation-dependent signaling, including PKC, MAPK, and phosphatidylinositol 3-kinase/PKB pathways, and also Ca 2ϩ -dependent activation of calmodulin and myosin light chain kinase (4,9,29,31,33,35).…”

Fetal Cerebrovascular Maturation: Effects of Hypoxia

“…For VEGF, receptor levels for both the FLT and FLK types are expressed at lower levels in fetal than adult arteries, and hypoxia dramatically increases both receptor types in both age groups 37,38 . Hypoxia also increases expression of endothelin-A receptors in fetal cerebral arteries 36 .…”

“…In cerebral arteries upstream of the microcirculation, hypoxia causes significant changes in composition, including increases in wall thickness and protein content in a manner that is graded with the severity and duration of hypoxia 18,30–32 . Age is also a critical factor in remodeling responses to hypoxia 33–35 due in large part to developmental and maturational differences in the populations of cell surface receptors on the smooth muscle cells for both RTK-dependent and GPCR dependent vasotrophic factors such as VEGF 15 and endothelin-1 19,36 . For VEGF, receptor levels for both the FLT and FLK types are expressed at lower levels in fetal than adult arteries, and hypoxia dramatically increases both receptor types in both age groups 37,38 .…”

“…Conversely, hypoxia also promotes the growth and expansion of the perivascular adrenergic innervation, which helps maintain contractile differentiation of cerebrovascular smooth muscle 48,185 . However, in aggregate these hypoxic changes yield a cerebrovasculature that is generally less reactive and slower to respond to changes in blood pressure, blood gases and other contractile stimuli than typical of a healthy normoxic fetus 36,41,161 . What then, is the best strategy to manage an infant that has suffered but survived in utero or perinatal hypoxia?…”

“…Correspondingly, antagonism of the PDGF receptor following intracerebral hemorrhage has proven to help preserve contractile differentiation and reduce overall cerebral injury 193 . A variety of G-Protein Coupled Receptors, including those activated by endothelin 36 and angiotensin II 59 , also potently influence contractile differentiation, although the effects of inhibitors of these peptides have yet to be investigated in the context of hypoxic-ischemic injury in the immature brain. Finally, recent discoveries that multiple miRNA molecules, including miR-1 194 , miR-29c 195 , miR-145 196 , and potentially many others 197 can significantly influence smooth muscle phenotype.…”