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Hypoxic stress is a common occurrence during human pregnancy, yet little is known about its effects on the fetal brain. This study examined the fetal hemodynamic responses to chronic hypoxia in an experimental mouse model of chronic maternal hypoxia (11% O 2 from E14.5 to E17.5). Using high-frequency Doppler ultrasound, we found fetal cerebral and ductus venosus blood flow were both elevated by 69% and pulmonary blood flow was decreased by 62% in the fetuses exposed to chronic hypoxia compared to controls. This demonstrates that brain sparing persists during chronic fetal hypoxia and is mediated by "streaming," where highly oxygenated blood preferentially flows through the ductus venosus towards the cerebral circulation, bypassing the liver and the lungs. Consistent with these changes in blood flow, the fetal brain volume measured by MRI is preserved, while the liver and lung volumes decreased compared to controls. However, hypoxia exposed fetuses were rendered vulnerable to an acute hypoxic challenge (8% O 2 for 3 min), demonstrating global blood flow decreases consistent with imminent fetal demise rather than elevated cerebral blood flow. Despite this vulnerability, there were no differences in adult brain morphology in the mice exposed to chronic maternal hypoxia compared to controls.

Aerobic activity has been shown highly beneficial to brain health, yet much uncertainty still surrounds the effects of exercise on the functioning of cerebral microvasculature. This study used two-photon fluorescence microscopy to examine cerebral hemodynamic alterations as well as accompanying geometric changes in the cortical microvascular network following five weeks of voluntary exercise in transgenic mice endogenously expressing tdTomato in vascular endothelial cells to allow visualization of microvessels irrespective of their perfusion levels. We found a diminished microvascular response to a hypercapnic challenge (10% FiCO 2 ) in running mice when compared to that in nonrunning controls despite commensurate increases in transcutaneous CO 2 tension. The flow increase to hypercapnia in runners was 70% lower than that in nonrunners (p = 0.0070) and the runners' arteriolar red blood cell speed changed by only half the amount seen in nonrunners (p = 0.0085). No changes were seen in resting hemodynamics or in the systemic physiological parameters measured. Although a few unperfused new vessels were observed on visual inspection, running did not produce significant morphological differences in the microvascular morphometric parameters, quantified following semiautomated tracking of the microvascular networks. We propose that voluntary running led to increased cortical microvascular efficiency and desensitization to CO 2 elevation.

Cerebral ischemia is a significant source of morbidity in children with sickle cell anemia; however, the mechanism of injury is poorly understood. Increased cerebral blood flow and low hemoglobin levels in children with sickle cell anemia are associated with increased stroke risk, suggesting that anemia-induced tissue hypoxia may be an important factor contributing to subsequent morbidity. To better understand the pathophysiology of brain injury, brain physiology and morphology were characterized in a transgenic mouse model, the Townes sickle cell model. Relative to age-matched controls, sickle cell anemia mice demonstrated: (1) decreased brain tissue pO 2 and increased expression of hypoxia signaling protein in the perivascular regions of the cerebral cortex; (2) elevated basal cerebral blood flow , consistent with adaptation to anemia-induced tissue hypoxia; (3) significant reduction in cerebrovascular blood flow reactivity to a hypercapnic challenge; (4) increased diameter of the carotid artery; and (5) significant volume changes in white and gray matter regions in the brain, as assessed by ex vivo magnetic resonance imaging. Collectively, these findings support the hypothesis that brain tissue hypoxia contributes to adaptive physiological and anatomic changes in Townes sickle cell mice. These findings may help define the pathophysiology for stroke in children with sickle cell anemia.

Genetic and surgical mouse models are commonly used to study cerebrovascular disease, but their size makes invasive hemodynamic testing technically challenging. The purpose of this study was to demonstrate a noninvasive measurement of cerebrovascular impedance and wave reflection in mice using high-frequency ultrasound in the left common carotid artery (LCCA), and to examine whether microvascular changes associated with hypercapnia could be detected with such an approach. Ten mice (C57BL/6J) were studied using a high-frequency ultrasound system (40 MHz). Lumen area and blood flow waveforms were obtained from the LCCA and used to calculate pulse-wave velocity, input impedance, and reflection amplitude and transit time under both normocapnic and hypercapnic (5% CO2) ventilation. With hypercapnia, vascular resistance was observed to decrease by 87%±12%. Although the modulus of input impedance was unchanged with hypercapnia, a phase decrease indicative of increased total arterial compliance was observed at low harmonics together with an increased reflection coefficient in both the time (0.57±0.08 versus 0.68±0.08, P=0.04) and frequency domains (0.62±0.08 versus 0.73±0.06, P=0.02). Interestingly, the majority of LCCA blood flow was found to pass into the internal carotid artery (range=76% to 90%, N=3), suggesting that hemodynamic measurements in this vessel are a good metric for intracerebral reactivity in mouse.

Mice reproduce many features of human pregnancy and have been widely used to model disorders of pregnancy. However, it has not been known whether fetal mice reproduce the physiologic response to hypoxia known as brain sparing, where blood flow is redistributed to preserve oxygenation of the brain at the expense of other fetal organs. In the present study, blood oxygen level-dependent (BOLD) magnetic resonance imaging (MRI) and Doppler ultrasound were used to determine the effect of acute hypoxia on the fetal blood flow in healthy, pregnant mice. As the maternal inspired gas mixture was varied between 100% and 8% oxygen on the timescale of minutes, the BOLD signal intensity decreased by 44±18% in the fetal liver and by 12±7% in the fetal brain. Using Doppler ultrasound measurements, mean cerebral blood velocity was observed to rise by 15±8% under hypoxic conditions relative to hyperoxia. These findings are consistent with active regulation of cerebral oxygenation and clearly show brain sparing in fetal mice.