Pathologies of the micro- and macrovascular systems are a hallmark of the metabolic syndrome, which can lead to chronically elevated blood pressure. However, the underlying pathomechanisms involved still need to be clarified. Here, we report that an obesity-associated increase in serum leptin triggers the select expansion of the micro-angioarchitecture in pre-autonomic brain centers that regulate hemodynamic homeostasis. By using a series of cell- and region-specific loss- and gain-of-function models, we show that this pathophysiological process depends on hypothalamic astroglial hypoxia-inducible factor 1α-vascular endothelial growth factor (HIF1α-VEGF) signaling downstream of leptin signaling. Importantly, several distinct models of HIF1α-VEGF pathway disruption in astrocytes are protected not only from obesity-induced hypothalamic angiopathy but also from sympathetic hyperactivity or arterial hypertension. These results suggest that hyperleptinemia promotes obesity-induced hypertension via a HIF1α-VEGF signaling cascade in hypothalamic astrocytes while establishing a novel mechanistic link that connects hypothalamic micro-angioarchitecture with control over systemic blood pressure.
GrantsEuropean Research Council (AdG grant Hypoflam) German Research Foundation under Germany's Excellence Strategy Helmholtz Excellence Network US National Institutes of Health Department of Veterans Affairs University of Iowa Fraternal Order of Eagles Diabetes Research Center Iowa Neuroscience Institute Technische UniversitaEurot MuEuronchen - Institute for Advanced Study - German Excellence Initiative European Union Seventh Framework Programme European Research Council (STG grant AstroNeuroCrosstalk) German Research Foundation Marie SklodowskaCurie grant