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Proteomic mapping reveals dysregulated angiogenesis in the cerebral arteries of rats with early-onset hypertension

ABSTRACT: Using data-independent acquisition-based mass spectrometry analysis, we determined the protein changes in cerebral arteries in pre- and early-onset hypertension from the spontaneously hypertensive rat (SHR), a model that resembles essential hypertension. Our analysis identified 125 proteins with expression levels that were significantly up- or downregulated in 12-week old SHRs compared to normotensive Wistar Kyoto rats. Using an angiogenesis enrichment analysis, we identified a critical imbalance in angiogenic proteins, promoting an anti-angiogenic profile in cerebral arteries at the early-onset of hypertension. In a comparison to previously published data, we demonstrate that this angiogenic imbalance is not present in mesenteric and renal arteries from age-matched SHRs. Finally, we identified two proteins (Fbln5 and Cdh13), whose expression levels were critically altered in cerebral arteries compared to the other arterial beds. The observation of an angiogenic imbalance in cerebral arteries from the SHR reveals critical protein changes in the cerebrovasculature at the early-onset of hypertension and provides novel insight into the early pathology of cerebrovascular disease.

INSTRUMENT(S): timsTOF

ORGANISM(S): Rattus Norvegicus (rat)

TISSUE(S): Cerebral Artery

SUBMITTER: Joakim Bastrup

LAB HEAD: Thomas Jepps

PROVIDER: PXD040818 | Pride | 2023-09-20

REPOSITORIES: Pride

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Project description:Background: The vascular wall of small arteries is heavily affected by high blood pressure. However, the underlying mechanisms causing vascular changes are not fully elucidated. Using a novel data-independent acquisition mass spectrometry (DIA-MS) approach, we aimed to determine the proteomic changes in small mesenteric arteries during early-onset high blood pressure in a rat model of hypertension. Methods: Snap frozen small mesenteric and renal arteries from the spontaneous hypertension rat (SHR) model and Wistar Kyoto (WKY) control rats were collected from two time points (6- and 12-weels of age) and analyzed by a label free quantitative DIA-MS workflow. Mesenteric arteries from Wister Hannover rats were included as an additional control to clarify genetic drift caused by selective inbreeding. Results: We identified a total of 3956 consistent proteins in the mesenteric artery wall and found that 286 proteins were significantly regulated in 12-weeks old SHRs compared to WKY controls. Comparing to an in silico matrisome database, we identified 38 extracellular matrix-associated proteins that could distinguish SHRs from WKY controls. Furthermore, when comparing the significantly regulated proteins identified in mesenteric and renal arteries, we identified 18 proteins, including Serpina3l, Igg-2a, ENSRNOG00000049829, Acyp2, Enpp3, Lss, Acaa1a, Basp1, an isoform of Basp1, Flot1, Flot2, Gstt1, Nit1, Ppid, Ikbkap, Poglut3, P4ha2 and Usp15, that were changed in both vascular beds. These proteins were associated with vital cellular processes, such as dyslipidemia, protease inhibition, remodeling and generation of reactive oxygen species. Majority of the identified proteins and pathways were associated with hypertension, and mapping the underlying changes help understanding the pathological processes occurring in the arterial wall during early-onset hypertension. Conclusions: Our data provides an in-depth analysis of the proteomic architecture of the mesenteric and renal artery wall from SHRs and WKY control rats. We identified 18 novel candidate proteins that highlights critical changes in small arteries of the SHR.

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Proteomic mapping reveals dysregulated angiogenesis in the cerebral arteries of rats with early-onset hypertension

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