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Fetal Hypoxia Suppresses TRPC6 and Impairs Cerebral Autoregulation in Neonatal Rats.

Xiangqun Hu,Rui Song,C. Dasgupta,A. Blood,Lubo Zhang

Published 2025 in Stroke

ABSTRACT

BACKGROUND Cerebrovascular pressure autoregulation is the physiological mechanism that maintains cerebral blood flow (CBF) relatively constant across changes in cerebral perfusion pressure. It is a vital protective mechanism of the brain during fluctuations in arterial blood pressure that is particularly volatile in newborn infants. Yet, much remains unknown of the mechanisms underlying CBF autoregulation in the infant brain. METHODS Time-dated pregnant Sprague-Dawley rats were randomly divided into the normoxic control group and continuous hypoxic exposure group (10.5% oxygen) from day 15 to 21 of gestation. Rat pups were raised in normoxic conditions after birth. We tested the hypothesis that TRPC6 (transient receptor potential canonical channel 6) plays a key role in CBF autoregulation in the neonatal brain using postnatal days 12 to 14 rat pups. Blood pressure and CBF were measured. TRPC6 and CaV1.2 expression and activity were assessed. RESULTS We demonstrated that TRPC6 functions as a mechanosensor to stretch the cell membrane and modulates CaV1.2 activity of the middle cerebral artery in the neonatal rat brain. Fetal hypoxia downregulated TRPC6 expression/activity, TRPC6-CaV1.2 coupling, and CBF autoregulation in the neonate. The loss-of-function approach using TRPC6 knockdown by siRNA and pharmacological TRPC6 inhibition recapitulated the effect of fetal hypoxia on the impairments of CBF autoregulation in neonatal pups. CONCLUSIONS Our findings provide novel insights into the mechanism of CBF autoregulation in newborn brains and highlight a critical role of TRPC6 dysfunction in impaired cerebral autoregulation and heightened vulnerability to brain injury that is observed in the infant exposed to fetal hypoxia.

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