Hu Xiang-Qun, Song Rui, Dasgupta Chiranjib, Blood Arlin B, Zhang Lubo
Department of Basic Sciences, Lawrence D. Longo, MD Center for Perinatal Biology, Loma Linda University School of Medicine, CA. (X.-Q.H., R.S., C.D., A.B.B., L.S.).
Division of Neonatology, Department of Pediatrics, Loma Linda University School of Medicine, CA. (A.B.B.).
Stroke. 2025 Sep 17. doi: 10.1161/STROKEAHA.125.052524.
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.
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 Ca1.2 expression and activity were assessed.
We demonstrated that TRPC6 functions as a mechanosensor to stretch the cell membrane and modulates Ca1.2 activity of the middle cerebral artery in the neonatal rat brain. Fetal hypoxia downregulated TRPC6 expression/activity, TRPC6-Ca1.2 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.
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.
脑血管压力自动调节是一种生理机制，可在脑灌注压变化时维持脑血流量（CBF）相对恒定。在动脉血压波动期间，这是大脑至关重要的保护机制，而动脉血压波动在新生儿中尤为剧烈。然而，关于婴儿大脑中CBF自动调节的潜在机制仍有许多未知之处。
将怀孕的定时Sprague-Dawley大鼠从妊娠第15天至21天随机分为常氧对照组和持续低氧暴露组（10.5%氧气）。出生后的幼鼠在常氧条件下饲养。我们使用出生后第12至14天的幼鼠，检验了瞬时受体电位阳离子通道6（TRPC6）在新生大脑CBF自动调节中起关键作用的假设。测量血压和CBF。评估TRPC6和Ca1.2的表达及活性。
我们证明TRPC6作为一种机械传感器发挥作用，可拉伸细胞膜并调节新生大鼠大脑中脑动脉的Ca1.2活性。胎儿缺氧下调了新生大鼠的TRPC6表达/活性、TRPC6-Ca1.2偶联以及CBF自动调节功能。使用小干扰RNA敲低TRPC6和药理学抑制TRPC6的功能丧失方法重现了胎儿缺氧对新生幼鼠CBF自动调节功能损害的影响。
我们的研究结果为新生大脑中CBF自动调节机制提供了新的见解，并突出了TRPC6功能障碍在脑自动调节受损以及暴露于胎儿缺氧的婴儿中对脑损伤易感性增加方面的关键作用。
