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Hypertension has stage-dependent signatures in the hypertensive rat frontal brain

ABSTRACT: Long-term arterial hypertension causes cerebral microvascular dysfunction and doubles dementia risk in aging. However, cognitive health preservation by therapeutical blood pressure lowering alone might be limited by disease duration, the degree of irreversible tissue damage and whether microvascular function can be restored. This study aimed to understand cellular and molecular temporo-spatial pathomechanisms in the course of arterial hypertension. We investigated initial, early chronic and late chronic hypertension effects in the frontal brain of hypertensive rats by applying behavioral tests, histology, immunofluorescence, FACS and microvascular/neural tissue RNA sequencing as well as 18F-FDG PET imaging. Chronic hypertension caused frontal brain-specific behavioral deficits. From a mechanistic perspective our results suggest continuous microvascular stress and wounding due to hypertension, which in turn leads to an early recruitment of activated microglia and peripheral immune cells, blood-brain-barrier breakdown and an energy-demanding hypermetabolic state. Vascular adaptation mechanisms e.g., vessel wall strengthening by production of cellular adhesion molecules and extracellular matrix (ECM), and angiogenesis were first observed first in late chronic stages. Additionally, we identified late-chronic vascular accumulation of Igfbp-5 in the brains of rats and humans with hypertensive cerebral small vessel disease, possibly attenuating protective Igf-1 signaling in the cerebral microvasculature. Thus, we characterized cellular and molecular temporo-spatial pathomechanisms in the course of arterial hypertension, that might represent critical points for clinical decision-making and could therefore be used to prevent irreversible tissue damage.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE223851 | GEO | 2026/01/01

REPOSITORIES: GEO

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Project description:Human herpesvirus-8 (HHV-8) is the causative agent of Kaposiâs sarcoma and is associated with the angioproliferative disorders primary effusion lymphoma (PEL) and multicentric Castlemanâs disease (MCD). We have previously described evidence of HHV-8 infection within the pulmonary vasculature of patients with idiopathic pulmonary arterial hypertension (IPAH). We speculated that viral infection of the pulmonary microvascular endothelial cells could cause the angioproliferative phenotype characteristic of severe pulmonary arterial hypertension (PAH). We now demonstrate the ability of HHV-8 to infect human pulmonary microvascular endothelial cells (HPMVECs) in vitro, confirming both latent and lytic infection. HHV-8 infection of HPMVECs resulted in significant changes of gene expression including alterations of pathways integral to both cellular apoptosis and angiogenesis. This infection also results in alterations of genes integral to the bone morphogenic protein (BMP) pathway, including down regulation of bone morphogenic protein receptor 1a (BMPR1a) and bone morphogenic protein 4 (BMP4). Other genes previously implicated in the development of PAH are also altered in expression by HHV-8 infection. These include increased expression of Interleukin-6 (IL-6) and the matrix metalloproteinases (MMP)-1, MMP-2 and MMP-10. Lastly, cells infected with HHV-8 apoptosis resistant. Infection of pulmonary microvascular endothelial cells with human herepesvirus-8 results in alteration of the BMP pathway as well as an anti-apoptotic phenotype, consistent with the development of plexiform lesions characteristic of pulmonary arterial hypertension. Experiment Overall Design: â¢ Direct comparison of HHV8-infected and mock-infected human pulmonary microvascular endothelial cells. Experiment Overall Design: â¢ Triplicate infection and mock infection samples were prepared. One hybridization per sample, 6 total hybridizations Experiment Overall Design: â¢ Single channel hybridization (no reference).

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Hypertension has stage-dependent signatures in the hypertensive rat frontal brain

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