Abstract WMP32: Osteoprotegerin Attenuates the Growth of Intracranial Aneurysms Activating Collagen Biosynthesis and Vascular Smooth Muscle Cell Proliferation via Transforming Growth Factor-Beta1 Signaling

Abstract

Introduction: The pathogenesis of intracranial aneurysms (IAs) are characterized by reduced extracellular matrix and decreased number of vascular smooth muscle cells (VSMCs) in cerebral vascular walls. It is previously reported that osteoprotegerin (OPG) increase collagen content and activate VSMCs proliferation via transforming growth factor-beta1 (TGF-beta1). We investigated whether to attenuate IAs growth through the effect of OPG on collagen expression and VSMCs proliferation in IAs model rats. Materials and Methods: IAs were surgically induced in 7-week-old male Sprague Dawley rats. 1 week after the operation, mouse recombinant OPG at 125 μg/mL or vehicle was continuously infused into the lateral ventricle via an osmotic pump. 5 weeks after the first operation, aneurysmal size, media thickness of IAs were measured in the both groups. The expression of type-I and type-III collagen, TGF-beta1 and phosphorylated Smad2/3 in IA walls were examined by immunohistochemistry and RT-PCR. Primary cell culture of mouse VSMCs were analyzed by RT-PCR and the cell proliferation assay with SB431542 (a selective TGF-β receptor I inhibitor). Results: In the OPG treatment group, size and media thickness ratio of IAs were significantly smaller (control vs. OPG: 42 ± 6.5 μm vs 66 ± 6.1 μm; P < 0.05) and higher (control vs. OPG: 55 ± 7 % vs 34 ± 3 %; P < 0.05) than in the vehicle-control group. In the immunohistochemistry, collagen and phosphorylated Smad2/3 were upregulated in IA walls in the OPG group. In the RT-PCR study, OPG treatment significantly upregulated expression of collagen and TGF-beta1 genes ( P < 0.05). In mouse VSMC cultures, OPG administration enhanced the expression of collagen and TGF-β1 genes. The cell proliferation assay revealed the OPG administration promoted VSMCs proliferation and SB431542 canceled this effect ( P < 0.05). Conclusions: Our results demonstrate that OPG has a suppressive effect on IAs growth through the activation of collagen biosynthesis and VSMC proliferation via TGF-beta1 signaling in IA walls. OPG may represent a novel therapeutic target of the medical treatment for IAs.