Endogenously elicited antibodies to platelet derived growth factor-BB and platelet cytosolic protein inhibit aortic lesion development in the cholesterol-fed rabbit.

Abstract

Several studies have indicated that growth factors, such as platelet derived growth factor (PDGF), may be important in atherogenesis. These factors are released from platelets, or expressed by cells of the arterial wall. In order to study their role in atherogenesis more directly, rabbits were immunized with PDGF-BB, platelet cytosolic protein, or human serum albumin (HSA), until high titres of antibody were attained. Atherosclerotic lesions were subsequently induced by feeding the animals with a 2% cholesterol enriched diet. At the end of approximately 3 months, the extent of aortic lesion development was assessed by image analysis of en face preparations of aortae stained with Oil Red-O, and histological segments of aortae taken at the level of the first intercostal artery branch point. The endogenous antibodies were characterized with respect to their cross-reactivity, and ability to neutralize PDGF and platelet cytosol-induced cell proliferation and migration in vitro. The endogenous, anti-PDGF-BB antibody was isoform specific, and neutralized the mitogenic and chemotactic properties of PDGF-BB and rabbit platelet cytosolic protein in vitro. The anti-platelet cytosol antibody partially inhibited the chemotactic and mitogenic properties of rabbit platelet cytosolic protein. Compared to non-immune rabbits (n = 5), animals immunized with HSA (n = 4) had a significantly larger area of aortic lesion involvement (P < 0.01), whereas aortic lesions in rabbits immunized with PDGF-BB (n = 5), or platelet cytosolic protein (n = 7) were significantly smaller than either non-immune animals, or animals immunized with HSA (P < 0.05). The same pattern was observed for other measures of aortic lesion involvement including aortic intima:media ratio at the level of the first intercostal artery. These data suggest that PDGF-BB, and possibly other platelet-associated growth factors, are involved in cholesterol-induced atherosclerosis.