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; De Bernardis Murat, Cahuê; Le Thuc, Ophelia; Legutko, Beata; Ruiz-Ojeda, Francisco J; Fuente-Fernández, María de la; García-Villalón, Angel Luis; González-Hedström, Daniel; Huber, Melanie; Szigeti-Buck, Klara; Müller, Timo D; Ussar, Siegfried; Pfluger, Paul; Woods, Steve C; Ertürk, Ali; LeDuc, Charles A; Rahmouni, Kamal; Granado, Miriam; Horvath, Tamas L; Tschöp, Matthias H; García-Cáceres, Cristina     «

Gruber, Tim; Pan, Chenchen; Contreras, Raian E; Wiedemann, Tobias; Morgan, Donald A; Skowronski, Alicja A; Lefort, Sandrine; De Bernardis Murat, Cahuê; Le Thuc, Ophelia; Legutko, Beata; Ruiz-Ojeda, Francisco J; Fuente-Fernández, María de la; García-Villalón, Angel Luis; González-Hedström, Daniel; Huber, Melanie; Szigeti-Buck, Klara; Müller, Timo D; Ussar, Siegfried; Pfluger, Paul; Woods, Steve C; Ertürk, Ali; LeDuc, Charles A; Rahmouni, Kamal; Granado, Miriam; Horvath, Tamas L; Tschöp, Matthias...     »

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.      «

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 m...     »