Effects of chronic hypoxia on cerebral blood flow autoregulation in the newborn

The National Institutes of Health National Heart Lung and Blood Institute awarded Loma Linda University $776,881 on June 15, 2026, under the Cardiovascular Diseases Research program (CFDA 93.837) to investigate the effects of chronic hypoxia on cerebral blood flow autoregulation in newborns.

The research defines the role of mechanosensitive cation channel TRPC6 and the voltage-sensitive L-type calcium channel CAV1.2 in mediating the myogenic component of cerebral autoregulation in the newborn brain. The project uses a clinically relevant newborn lamb model to characterize how chronic perinatal hypoxia disrupts this pathway and to determine the role of microRNA-210 and mitochondrial reactive oxygen species in mediating hypoxia-induced impairment of cerebral autoregulation. The study integrates molecular, cellular, and whole-animal approaches to advance understanding of physiological mechanisms underlying neonatal cerebral autoregulation and their disruption by hypoxia, with the long-term goal of identifying novel therapeutic targets to preserve or restore cerebral autoregulation.

Performance of work occurs in Loma Linda, California. The period of performance runs from the award date through February 28, 2030. The assistance type is a Project Grant.

Abstract

Cerebral autoregulation (CA) is a vital physiological mechanism that ensures stable cerebral blood flow (CBF) despite fluctuations in systemic blood pressure. In the newborn, especially during the perinatal period, failure of CA is strongly associated with devastating brain injuries such as intraventricular hemorrhage (IVH) and periventricular leukomalacia (PVL), leading to lifelong neurodevelopmental impairments. Despite the clinical significance of impaired CA, the underlying molecular mechanisms, particularly in the context of perinatal hypoxia, are poorly understood. This proposal aims to define the role of the mechanosensitive cation channel TRPC6 and its downstream target, the voltage-sensitive l-type CAV1.2 CA²⁺ channel (CAV1.2), in mediating the myogenic component of CA in the newborn brain. Preliminary findings suggest that TRPC6 channels are essential for pressure-induced vasoconstriction in cerebral arteries of newborn rodents and lambs. The project further investigates how chronic perinatal hypoxia impairs this mechanism, with a focus on the epigenetic regulator microrna-210 (MIR210), a known hypoxia-induced molecule that may suppress TRPC6 expression and enhance mitochondrial reactive oxygen species (ROS) production, both of which could disrupt CA. Using a clinically relevant newborn lamb model, the proposed research will: (1) define the contributions of TRPC6 and CAV1.2 channels to CA in vivo and in vitro; (2) characterize how chronic perinatal hypoxia disrupts this pathway; and (3) determine the role of MIR210 and mitochondrial ROS in mediating hypoxia-induced impairment of CA. By integrating molecular, cellular, and whole-animal approaches, this study will advance understanding of the physiological mechanisms underlying neonatal CA and their disruption by hypoxia. The long-term goal is to identify novel therapeutic targets to preserve or restore CA in vulnerable neonates, thereby reducing the incidence of hypoxia-related brain injury and improving neurodevelopmental outcomes.