Abstract 9460: Effects of Milk Fat Globule Epidermal Growth Factor VIII on Adverse Aortic Remodeling in Mice With Advancing Age

Abstract

Background: Milk fat globule epidermal growth factor VIII (MFG-E8), a secreted membrane glycoprotein, is an inflammatory signaling molecule, promoting the proliferation and invasion of vascular smooth muscle cells in vitro. MFG-E8 also is a bridging molecule that connects vascular smooth muscle cells to elastic fibers, forming elastin-smooth muscle unit, an essential contractile element within arterial medial wall. The inflammatory effects of MFG-E8 signaling between cells and matrix on adverse arterial remodeling with advancing age, however, remains unknown. Methods and Results: In this study, homozygous MFG-E8 knockout (MFG-E8 KO, n=50) and age-matched wild type male mice (WT, n=50) were investigated. Western blot analysis confirmed that MFG-E8 protein was enriched in the aortic walls of WT mice, but not detected in MFG-E8 KO animals (Fig. A) . In WT, aortic MFG-E8 protein was markedly increased (~18-fold, p<0.0001) in 96-week-old versus 40-week-old ( Fig. B ). Importantly, aortic elastin proportion (an index of elastin degradation) was significantly decreased in 96-week- versus 40-week-old while both collagen and calcium deposits proportion were markedly increased in WT mice; however, MFG-E8 deficiency significantly alleviated these age effects ( Fig. C ). The procalcification proteins alkaline phosphatase (ALP) and runt-related transcription factor 2 (Runx2) were markedly increased in 96-week-old WT versus MFG-E8 KO ( Fig. D ). Notably, MFG-E8 deficiency slightly effected on age-associated change in systolic blood pressure (SBP) compared to WT ( Fig. E) and significantly extended the lifespan compared to WT (p=0.032) ( Fig. F ). Conclusion: These findings suggest that MFG-E8 signaling links cells and matrix to age-associated adverse arterial remodeling, including elastin degradation, collagen deposition, and calcification. Thus, the MFG-E8 knockout has beneficial effects on arterial health during advancing age and prolongs the lifespan in mice.