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 2

Matrisome protein accumulation with ectopic elastic lamina formation in the intima of the cerebral arteries of HTRA1–/– mice.

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Matrisome protein accumulation with ectopic elastic lamina formation in ...
(A) Matrisome protein levels in the anterior and middle cerebral arteries were assessed by immunoblotting (n = 5–8 animals per group). The samples used for TIMP3 and fibulin-5 were identical and distinct from those used for the other matrisome protein quantifications. The bar graphs show values relative to those for HTRA1+/+ mice. (B–D) Immunohistochemical detection of FN (B), LTBP-4 (C), and fibulin-5 (D) in the anterior cerebral arteries at 24 months of age. Autofluorescence, A.F. Scale bars = 50 μm. Bar graphs show the quantification of FN-, LTBP-4-, and fibulin-5-immunopositive areas. The FN-, LTBP-4–, and fibulin-5–positive areas in the vessel wall in each image were quantified and normalized to the outer circumference of the vessel to eliminate the effects of vascular dilation in HTRA1−/− mice (n = 5–6 animals per group). (E) Simultaneous immunohistochemical detection of elastin and LTBP-4 in the anterior cerebral arteries. Three mice per group were analyzed. Ectopic elastic lamina formation was observed in all HTRA1−/− mice. Typical images are shown. Scale bars = 10 μm. The data represent the mean ± SD. **P < 0.01 and ***P < 0.001 with 2-tailed unpaired t test or the Mann-Whitney U test (A–D).