Obesity-associated hyperleptinemia alters the gliovascular interface of the hypothalamus to promote hypertension

Gruber, Tim; Pan, Chenchen; Contreras, Raian E.; Wiedemann, Tobias; Morgan, Donald A.; Skowronski, Alicja A.; Lefort, Sandrine; Murat, Cahue De Bernardis; Le Thuc, Ophelia; Legutko, Beata; Ruiz-Ojeda, Francisco J.; de la Fuente-Fernandez, Maria; Garcia-Vil

Publicación: CELL METABOLISM
2021
VL / 33 - BP / 1155 - EP / +
abstract
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 1a-vascular endothelial growth factor (HIF1a-VEGF) signaling downstream of leptin signaling. Importantly, several distinct models of HIF1a-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 HIF1a-VEGF signaling cascade in hypothalamic astrocytes while establishing a novel mechanistic link that connects hypothalamic micro-angioarchitecture with control over systemic blood pressure.

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Hybrid, Green published