Targeting mTOR to Mitigate Sequelae of Chronic Hypoxia on the Carotid Artery and Cerebral Circulation

ABSTRACT

We hypothesized that vascular maladaptations resulting from chronic hypoxemia worsen end‐organ function via insidious positive feedback. To test this hypothesis in the systemic circulation, we quantified brain perfusion and left heart function and then biomechanically phenotyped the left common carotid artery (LCCA) in adult female mice under normoxic (21% oxygen) and chronic hypoxic (10%) conditions. Functional MRI revealed that hypoxia impaired cerebrovascular reactivity during transient hypercapnia (pCO ₂ 5%) while echocardiography revealed altered left ventricular diastolic, but not systolic, function. These end organ changes associated with an 18.8% decrease in distensibility of the LCCA due to a 34.4% increase in circumferential material stiffness without an increase in wall thickness. This finding suggested a change in the state (e.g., collagen microstructure), not amount, of the LCCA extracellular matrix. Active biaxial testing of the LCCA further revealed up to an 11% reduction of SMC contractility in response to vasoactive agents. Treatment with the mTOR inhibitor rapamycin improved LCCA properties in hypoxic mice, as reflected by a 53.37% increase in distensibility and a 43% improvement in contractility relative to the hypoxic group. We conclude that chronic hypoxia causes multiorgan effects: stiffer carotid arteries having impaired vascular reactivity associate with impaired cerebral and cardiac function. Maladaptive LCCA changes are prevented with mTOR inhibition during hypoxia, suggesting mTOR as a potential target to break the insidious feedback loop that leads to hypoxia‐induced maladaptive remodeling and to mitigate associated end‐organ dysfunction, with possible advantages to single ventricle patients who experience long periods of hypoxemia.