Loss of HtrA1-induced attenuation of TGF-β signaling in fibroblasts might not be the main mechanism of CARASIL pathogenesis

Abstract

Loss of HtrA1-induced attenuation of TGF-β signaling in fibroblasts might not be the main mechanism of CARASIL pathogenesisIn their contribution to PNAS, Beaufort et al. demonstrate that high temperature requirement protein A1 (HtrA1) facilitates TGF-β signaling through processing latent TGF-β binding protein 1 (LTBP-1) (1).Then the authors suggest the down-regulation of TGF-β signaling by lack of HtrA1-mediated LTBP-1 processing as a key mechanism underlying pathogenesis of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) (1).We applaud the authors for their careful work about HtrA1 but would like to point out that they only studied fibroblasts (FBs), and their data do not support a causative role of this novel mechanism for the pathogenesis of CARASIL.For CARASIL patients, the main pathology falls on the small penetrating arteries, with lack of vascular smooth muscle cells (VSMCs) in the media and intense adventitial fibrosis (2).Loss of VSMCs is the primary feature of CARASIL, followed by deposition of the granular material in the media and fibrosis of the arterial wall (2, 3).Arterial fibrosis results in the deficiency of contraction of the arteries,