AI Article Synopsis

  • Cerebral small vessel disease (CSVD) leads to dementia and movement issues, with CARASIL being a hereditary form caused by a loss of function in the HTRA1 enzyme.
  • In CARASIL, the disease results in changes to blood vessels, such as thickening and abnormal structure, which reduces blood flow in the brain.
  • Treatment with candesartan was found to reduce the accumulation of specific proteins linked to vascular structure and improve blood flow, suggesting potential targets for future therapies.

Article Abstract

Cerebral small vessel disease (CSVD) causes dementia and gait disturbance due to arteriopathy. Cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) is a hereditary form of CSVD caused by loss of high-temperature requirement A1 (HTRA1) serine protease activity. In CARASIL, arteriopathy causes intimal thickening, smooth muscle cell (SMC) degeneration, elastic lamina splitting, and vasodilation. The molecular mechanisms were proposed to involve the accumulation of matrisome proteins as substrates or abnormalities in transforming growth factor β (TGF-β) signaling. Here, we show that HTRA1-/- mice exhibited features of CARASIL-associated arteriopathy: intimal thickening, abnormal elastic lamina, and vasodilation. In addition, the mice exhibited reduced distensibility of the cerebral arteries and blood flow in the cerebral cortex. In the thickened intima, matrisome proteins, including the hub protein fibronectin (FN) and latent TGF-β binding protein 4 (LTBP-4), which are substrates of HTRA1, accumulated. Candesartan treatment alleviated matrisome protein accumulation and normalized the vascular distensibility and cerebral blood flow. Furthermore, candesartan reduced the mRNA expression of Fn1, Ltbp-4, and Adamtsl2, which are involved in forming the extracellular matrix network. Our results indicate that these accumulated matrisome proteins may be potential therapeutic targets for arteriopathy in CARASIL.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8592543PMC
http://dx.doi.org/10.1172/JCI140555DOI Listing

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