Abstract 277: Downregulation of PDGF-D is Associated with Increased Collagen Production in Abdominal Aortic Aneurysm

Abstract

BACKGROUND Abdominal aortic aneurysm (AAA) is characterized by loss of aortic smooth muscle cells (aoSMCs) and remodeling of extracellular matrix, such as collagen. Platelet-derived growth factor-D (PDGF-D) is the latest discovered member of the PDGF/VEGF family and involved in proliferation and migration of SMCs. Here we analyzed the expression of PDGF-D in human and murine AAA. Furthermore, we studied the potential role of PDGF-D in regulation of collagen in cultured aoSMC. METHOD AND RESULTS Gene expression analysis of abdominal aortas revealed a significant lower expression of PDGF-D (-85%) and its receptor PDGFR-β (-73%) in human aneurysmal wall compared to non-aneurysmal control aortas. PDGF-D and PDGFR-β was mainly localized to SMC and endothelial cells as determined by immunohistochemical analysis and was expressed weaker in aneurysmal samples compared with controls. In mice, luminal aortic diameter was increased by 60% (P<0.001) in aortas treated with 0.5M CaCl 2 compared to saline treated control aortas. In agreement with human AAA, PDGF-D expression was significantly decreased in mice with AAA (-60%) compared to controls. A decrease in the expression of PDGF-D was strongly correlated to both α-actin (r=0.95, P<0.001) and SM22α (r=0.94, P<0.001) expression. A decreased expression of PDGF-D (r=-0.76, P<0.05) and α-actin (r=-0.88, P<0.01) was correlated with increased expression of the apoptosis marker caspase-3. To investigate the potential inhibitory role of PDGF-D in collagen remodeling, cultured aoSMCs were stimulated with 20 ng/ml of human recombinant PDGF-D or PBS as control for 24 and 48 hours. Treatment of aoSMC with rh-PDGF-D resulted in a decrease in the synthesis of collagen-III (P=0.023) and -IV (P=0.01) as well as prolyl 4-hydroxylase (P=0.01) and lysyl oxidase (P=0.02) after 48 hours. The synthesis of collagen-I was unaffected with increased PDGF-D. CONCLUSION Our findings imply that PDGF-D functions as a negative regulator of collagen synthesis and that lack of PDGF-D could therefore be important for the AAA process.