| Abstrak/Abstract |
Homozygous mutations of human HTRA1 cause cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL). HtrA1-/- mice were examined for arterial abnormalities. Although their cerebral arteries were normal, the thoracic aorta was affected in HtrA1-/- mice. The number of vascular smooth muscle cells (VSMCs) in the aorta was increased in HtrA1-/- mice of 40 weeks or younger, but decreased thereafter. The cross-sectional area of the aorta was increased in HtrA1-/- mice of 40 weeks or older. Aortic VSMCs isolated from HtrA1-/- mice rapidly proliferated and migrated, produced high MMP9 activity, and were prone to oxidative stress-induced cell death. HtrA1-/- VSMCs expressed less smooth muscle ?-actin, and more vimentin and osteopontin, and responded to PDGF-BB more strongly than wild type VSMCs, indicating that HtrA1-/- VSMCs were in the synthetic phenotype. The elastic lamina was disrupted, and collagens were decreased in the aortic media. Calponin in the media was decreased, whereas vimentin and osteopontin were increased, suggesting a synthetic shift of VSMCs in vivo. Loss of HtrA1 therefore skews VSMCs toward the synthetic phenotype, induces MMP9 expression, and expedites cell death. We propose that the synthetic modulation is the primary event that leads to the vascular abnormalities caused by HtrA1 deficiency. |
