Candesartan prevents arteriopathy progression in cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy model
Taisuke Kato, … , Shoji Tsuji, Osamu Onodera
Taisuke Kato, … , Shoji Tsuji, Osamu Onodera
Published November 15, 2021
Citation Information: J Clin Invest. 2021;131(22):e140555. https://doi.org/10.1172/JCI140555.
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Research Article Neuroscience Vascular biology

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

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

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Figure 6

Candesartan prevents cerebral hypoperfusion in HTRA1–/– mice.

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Candesartan prevents cerebral hypoperfusion in HTRA1–/– mice. (A–C) Rest...
(A–C) Resting cerebral blood flow and response of cerebral blood flow to hypercapnia (10% CO2 inhalation) in HTRA1+/+ and HTRA1−/− mice with or without candesartan treatment measured by CASL using MRI at 16 to 20 months of age (n = 7 animals per group). (A and B) Resting cerebral blood flow in the cerebral cortex was calculated from regions of interest in the bilateral hemisphere, as indicated by red regions in (A). (A and C) Cerebral blood flow increase (%) in the cerebral cortex in response to hypercapnia. Cerebral blood flow during 10% CO2 inhalation was measured following measurement of resting cerebral blood flow. The data represent the mean ± SD. *P < 0.05 and **P < 0.01 with Bonferroni’s post hoc test (B).