Candesartan prevents arteriopathy progression in cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy model

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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.

Authors

Taisuke Kato, Ri-ichiroh Manabe, Hironaka Igarashi, Fuyuki Kametani, Sachiko Hirokawa, Yumi Sekine, Natsumi Fujita, Satoshi Saito, Yusuke Kawashima, Yuya Hatano, Shoichiro Ando, Hiroaki Nozaki, Akihiro Sugai, Masahiro Uemura, Masaki Fukunaga, Toshiya Sato, Akihide Koyama, Rie Saito, Atsushi Sugie, Yasuko Toyoshima, Hirotoshi Kawata, Shigeo Murayama, Masaki Matsumoto, Akiyoshi Kakita, Masato Hasegawa, Masafumi Ihara, Masato Kanazawa, Masatoyo Nishizawa, Shoji Tsuji, Osamu Onodera