Obesity-associated hyperleptinemia alters the gliovascular interface of the hypothalamus to promote hypertension.
Cell Metab. 2021 Apr 30:S1550-4131(21)00173-X. doi: 10.1016/j.cmet.2021.04.007. Epub ahead of print. PMID: 33951475.
|Authors/Editors:||Gruber T, Pan C, Contreras RE, Wiedemann T, Morgan DA, Skowronski AA, Lefort S, De Bernardis Murat C, Le Thuc O, Legutko B, Ruiz-Ojeda FJ, Fuente-Fernández M, García-Villalón AL, González-Hedström D, Huber M, Szigeti-Buck K, Müller TD, Ussar S, Pfluger P, Woods SC, Ertürk A, LeDuc CA, Rahmouni K, Granado M, Horvath TL, Tschöp MH, García-Cáceres C.|
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.