Knockin expression of human ADAMTS5 impairs cardiovascular development and aggravates cerebral cavernous...

ADAMTS5 is an enzyme that cleaves chondroitin sulfate proteoglycans such as versican (VCAN) and aggrecan (ACAN). The Adamts5-/- mouse model exhibits aortic anomalies, and increased expression of Adamts4 and Adamts5 leads to excessive versican degradation and reduced cardiac jelly. In zebrafish, knockdown of adamts5 rescues the cardiac phenotype conferred by ccm1 deficiency in zebrafish embryos. Here, we generated an ADAMTS5 knockin mouse model (ADAMTS5KI) to characterize the effect of induced expression of human ADAMTS5 on the cardiovascular system in mice. Sustained expression of ADAMTS5 in the endothelium diminished cardiac jelly formation and proteoglycan deposition in the atrioventricular cushion, and led to cardiac development arrest. Induced expression of ADAMTS5 in the endothelium of postnatal mice impaired cardiac valve patterning. Expression of ADAMTS5 in brain endothelial cells did not confer an obvious vascular defect. However, expression of ADAMTS5 in brain endothelial cells of Ccm2-deficient mice aggravated cerebral cavernous malformation (CCM) lesion burden and shortened the life span of Ccm2-deficient mice. These findings suggest that tight regulation of ADAMTS5 in the endothelium is essential for cardiovascular development and structural integrity, and that ADAMTS5 interacts with CCM signaling, contributing to CCM disease progression.