Abstract
Background: Structural components within the vasculature, including extracellular matrix proteins, play an integral role in modulating vascular homeostasis in health and disease. Previous studies have identified important roles of a family of secreted extracellular matrix associated proteins termed CCN (Cyr61, Ctgf, Nov) in mediating matrix homeostasis. However, a role for this family of proteins in the initiation / progression of vascular diseases remains undetermined. Methods and Results: Herein, biochemical and genetic gain- and loss-of function studies reveal a novel role for CCN3 (a member of the CCN family) in abdominal aorta aneurysm (AAA) biology. Current studies suggest CCN3 levels are reduced in the rodent aorta following angiotensin II (AngII) infusion, findings recapitulated in human AAA tissues. To address whether CCN3 deficiency affects the development of AAA, control C57BL/6 and CCN3-/- mice (n=30 per group) were subjected to AngII infusion. In response to four-week AngII infusion, the aortas of CCN3-/- mice demonstrated exquisite sensitivity with more than seventy percent of CCN3-/- mice developing visible AAA. Pathologically, the AAA phenotype of CCN3-/- mice was manifested as follows: (1) severe disruption of medial architecture characterized by prominent elastin degradation and vessel dilation; (2) a significant loss of smooth muscle cells; (3) a profound inflammatory response as evidenced by enhanced immune cell infiltration, increase expression of inflammatory markers; (4) heightened reactive oxygen species generation. Moreover, the AAA phenotype of CCN3-/- mice was confirmed in a second model of AAA formation (elastase perfusion). Next, bone marrow transplant experiments indicate the AAA phenotype of CCN3-/- mice is intrinsic to the vasculature. Furthermore, lentiviral mediated overexpression of CCN3 is sufficient to mitigate elastase-mediate AAA progression in mice. Mechanistically, genetic and pharmacological studies suggest the ERK1/2 pathway serves as an important role in the regulation of CCN3-dependent AAA development. Conclusions: These results demonstrate CCN3 as an essential regulator of AAA biology and suggest the potential for future therapeutic strategies by manipulating CCN3 levels.
Published Version
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