Journal
CELL METABOLISM
Volume 33, Issue 6, Pages 1155-+Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2021.04.007
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Funding
- Marie SklodowskaCurie grant [675610]
- European Research Council (AdG grant Hypoflam) [695054]
- German Research Foundation under Germany's Excellence Strategy [390857198]
- Helmholtz Excellence Network
- US National Institutes of Health [HL084207]
- Department of Veterans Affairs [BX004249]
- 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 [291763]
- European Research Council (STG grant AstroNeuroCrosstalk) [757393]
- German Research Foundation [SFB TRR152/P23, SFB TRR296]
- Marie Curie Actions (MSCA) [675610] Funding Source: Marie Curie Actions (MSCA)
- European Research Council (ERC) [757393] Funding Source: European Research Council (ERC)
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This study found that hyperleptinemia promotes obesity-induced hypertension through a HIF1a-VEGF signaling cascade in hypothalamic astrocytes. Blocking the HIF1a-VEGF pathway in astrocytes can protect from obesity-induced hypothalamic angiopathy, sympathetic hyperactivity, or arterial hypertension.
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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