Matricellular protein CCN3 mitigates abdominal aortic aneurysm.

1 2 8 2 jci.org Volume 126 Number 4 April 2016 Introduction Disruption of aortic homeostasis arising from genetic defects or exposure to environmental risk factors leads to localized abnormal widening of the aorta, a degenerative disease state termed aortic aneurysm that can affect the length of the aorta from its root to the abdominal segment (1, 2). Experimental studies reveal that aortic aneurysm is associated with compromised smooth muscle function, extracellular matrix (ECM) degradation, and increased vascular inflammation associated with leukocyte infiltration (2–6). This pathologic aortic milieu culminates with weakening of the vessel wall, a central characteristic of aortic aneurysm disease. Abdominal aortic aneurysm (AAA) is usually asymptomatic; however, rupture of an aortic aneurysm constitutes an important cause of mortality in the elderly that causes more than 15,000 deaths annually in the United States (WISQARS Leading Causes of Death Reports (1999– 2013); http://webappa.cdc. gov/sasweb/ncipc/leadcaus10_us. html). Despite the risk of mortality associated with AAA, there are no current drug therapies that have been shown to limit AAA development or progression (7). Currently, timely open or endovascular surgical repair remains the only form of treatment (8). Therefore, the elucidation of the cellular and molecular basis for this disease is imperative for the development of novel pharmacologic therapies and management strategies. In addition to providing structural support to the vasculature, the ECM is indispensable in modulating cellular signaling and vessel performance (9, 10). This ECM milieu dictates organismal health, while perturbation of ECM homeostasis is implicated in the development of pathological conditions, including atherosclerosis, restenosis, and AAA, with ECM proteins, such as collagen, elastin, and integrins, serving an essential role in mediating disease progression (11). However, despite considerable progress, identification of the molecular mechanisms underlying the ECMdependent modulation of vascular wall homeostasis in AAA initiation and progression remains incomplete. CCN (Cyr61, Ctgf, Nov) proteins are a group of secreted ECMassociated, partially identical cysteine-rich proteins that mediate diverse biologic functions (12–14). Although accumulating evidence demonstrates that the CCN gene family is critical to cell Abdominal aortic aneurysm (AAA) is a major cause of morbidity and mortality; however, the mechanisms that are involved in disease initiation and progression are incompletely understood. Extracellular matrix proteins play an integral role in modulating vascular homeostasis in health and disease. Here, we determined that the expression of the matricellular protein CCN3 is strongly reduced in rodent AAA models, including angiotensin II–induced AAA and elastase perfusion–stimulated AAA. CCN3 levels were also reduced in human AAA biopsies compared with those in controls. In murine models of induced AAA, germline deletion of Ccn3 resulted in severe phenotypes characterized by elastin fragmentation, vessel dilation, vascular inflammation, dissection, heightened ROS generation, and smooth muscle cell loss. Conversely, overexpression of CCN3 mitigated both elastaseand angiotensin II–induced AAA formation in mice. BM transplantation experiments suggested that the AAA phenotype of CCN3-deficient mice is intrinsic to the vasculature, as AAA was not exacerbated in WT animals that received CCN3-deficient BM and WT BM did not reduce AAA severity in CCN3-deficient mice. Genetic and pharmacological approaches implicated the ERK1/2 pathway as a critical regulator of CCN3-dependent AAA development. Together, these results demonstrate that CCN3 is a nodal regulator in AAA biology and identify CCN3 as a potential therapeutic target for vascular disease. Matricellular protein CCN3 mitigates abdominal aortic aneurysm