Rationale: Modulation of breathing by hypoxia accommodates variations in oxygen demand and supply during, for example, sleep and ascent to altitude, but the precise molecular mechanisms of this phenomenon remain controversial. Among the genes influenced by natural selection in high-altitude populations is one for the adenosine monophosphate-activated protein kinase (AMPK) a1-catalytic subunit, which governs cell-autonomous adaptations during metabolic stress.Objectives: We investigated whether AMPK-a1 and/or AMPK-a2 are required for the hypoxic ventilatory response and the mechanism of ventilatory dysfunctions arising from AMPK deficiency.Methods: We used plethysmography, electrophysiology, functional magnetic resonance imaging, and immediate early gene (c-fos) expression to assess the hypoxic ventilatory response of mice with conditional deletion of the AMPK-a1 and/or AMPK-a2 genes in catecholaminergic cells, which compose the hypoxia-responsive respiratory network from carotid body to brainstem.Measurements and Main Results: AMPK-a1 and AMPK-a2 deletion virtually abolished the hypoxic ventilatory response, and ventilatory depression during hypoxia was exacerbated under anesthesia. Rather than hyperventilating, mice lacking AMPK-a1 and AMPK-a2 exhibited hypoventilation and apnea during hypoxia, with the primary precipitant being loss of AMPK-a1 expression. However, the carotid bodies of AMPK-knockout mice remained exquisitely sensitive to hypoxia, contrary to the view that the hypoxic ventilatory response is determined solely by increased carotid body afferent input to the brainstem. Regardless, functional magnetic resonance imaging and c-fos expression revealed reduced activation by hypoxia of well-defined dorsal and ventral brainstem nuclei.Conclusions: AMPK is required to coordinate the activation by hypoxia of brainstem respiratory networks, and deficiencies in AMPK expression precipitate hypoventilation and apnea, even when carotid body afferent input is normal.

Background-Endoglin, an accessory receptor for transforming growth factor-␤ in vascular endothelial cells, is essential for angiogenesis during mouse development. Mutations in the human gene cause hereditary hemorrhagic telangiectasia type 1 (HHT1), a disease characterized by vascular malformations that increase with age. Although haploinsufficiency is the underlying cause of the disease, HHT1 individuals show great heterogeneity in age of onset, clinical manifestations, and severity. Methods and Results-In situ hybridization and immunohistochemical analysis of mouse and human hearts revealed that endoglin is upregulated in neoangiogenic vessels formed after myocardial infarction. Microvascularity within the infarct zone was strikingly lower in mice with reduced levels of endoglin (Eng ϩ/Ϫ ) compared with wild-type mice, which resulted in a greater deterioration in cardiac function as measured by magnetic resonance imaging. This did not appear to be because of defects in host inflammatory cell numbers in the infarct zone, which accumulated to a similar extent in wild-type and heterozygous mice. However, defects in vessel formation and heart function in Eng ϩ/Ϫ mice were rescued by injection of mononuclear cells from healthy human donors but not by mononuclear cells from HHT1 patients. Conclusions-These results establish defective vascular repair as a significant component of the origin of HHT1. Because vascular damage or inflammation occurs randomly, it may also explain disease heterogeneity. More generally, the efficiency of vascular repair may vary between individuals because of intrinsic differences in their mononuclear cells.

No abstract

White matter (WM) abnormalities, possibly resulting from hypoperfusion, are key features of the aging human brain. It is unclear, however, whether in vivo magnetic resonance imaging (MRI) approaches, such as diffusion tensor and magnetization transfer MRI are sufficiently sensitive to detect subtle alterations to WM integrity in mouse models developed to study the aging brain. We therefore investigated the use of diffusion tensor and magnetization transfer MRI to measure structural changes in 4 WM tracts following 1 month of moderate hypoperfusion, which results in diffuse WM pathology in C57Bl/6J mice. Following MRI, brains were processed for evaluation of white and gray matter pathology. Significant reductions in fractional anisotropy were observed in the corpus callosum (p = 0.001) and internal capsule (p = 0.016), and significant decreases in magnetization transfer ratio were observed in the corpus callosum (p = 0.023), fimbria (p = 0.032), internal capsule (p = 0.046) and optic tract (p = 0.047) following hypoperfusion. Hypoperfused mice demonstrated diffuse axonal and myelin pathology which was essentially absent in control mice. Both fractional anisotropy and magnetization transfer ratio correlate with markers of myelin integrity/degradation and not axonal pathology. The study demonstrates that in vivo MRI is a sensitive measure of diffuse, subtle WM changes in the murine brain.