Ischemic cerebral small-vessel disease is a common disorder in the elderly. However, little is known about the molecular basis of ischemic cerebral small-vessel disease. We recently found that mutations in the HtrA serine peptidase 1 (HTRA1) gene cause cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL). CARASIL is characterized by nonhypertensive cerebral small-vessel arteriopathy with alopecia and spondylosis. On neuropathologic examination, arteriosclerosis associated with intimal thickening and dense collagen fibers, loss of vascular smooth muscle cells, and hyaline degeneration of the media are observed in cerebral small arteries. These pathologic findings resemble those observed in patients with nonhereditary ischemic cerebral small-vessel disease. HTRA1 belongs to the HTRA protein family, the members of which have dual activities as chaperones and serine proteases. Studies have shown that members of the HTRA family repress transforming growth factor-Beta (TGF-Beta) family signaling. We found that CARASIL-associated mutant HTRA1s exhibited decreased protease activity and failed to repress TGF-Beta family signaling. Moreover, the amount of TGF-Beta1 was increased in the cerebral small arteries of CARASIL patients. In addition, the level of expression of ED-A fibronectin and versican, which is induced by TGF-Beta signaling, were accumulated in cerebral small arterial walls of a patient with CARASIL. Thus, we have concluded that the increased TGF-Beta signaling causes arteriopathy in CARASIL.