Abstract 4144768: Hypogenesis of Lymphatic Vessels in the Mitral Valve of Fibrillin-1 Mutant Mouse

Marfan Syndrome (MFS) is an autosomal-dominant cardiovascular disorder usually associated with the heterozygous mutation in the FBN1 gene, which encodes fibrillin-1, a structural macromolecule that polymerizes into microfibrils in connective tissue. Fibrillin-1 regulates the bioavailability of transforming growth factor (TGF) β1, a vital cytokine that modulates various cell activities. Enhanced TGFβ signaling induced by Fbn1 mutation is a major contributor to the MFS pathogenesis, one of which is myxomatous mitral valve degeneration that can cause mitral valve prolapse, with an incidence of about 45% in FBN1 mutant individuals. There is evidence that fibrillin microfibrils are present in the wall of lymphatic vessels, and that increased expression of TGFβ1 can inhibit lymphatic endothelial cell (LEC) proliferation during wound repair in mouse tail skin. We recently demonstrated the distribution and function of lymphatic vessels in murine mitral valves. However, the effects of FBN1 mutation on the formation and maintenance of lymphatic vessels in mitral valves have yet to be elucidated. To investigate the distribution and structure of lymphatic vessels in mitral valves of Fbn1 mutant mice, whole-mount immunostaining labeled with the LEC marker VEGFR3, as well as the endothelial markers CD31 and VE-cadherin, was performed on the mitral valves of adult (6-week-old) Fbn1 heterozygous mutant mice and their WT littermates. We found that the density of lymphatic vessels and the number of lymphatic branching points in mitral valve leaflets in Fbn1 heterozygous mutant mice were decreased, accompanied by the discontinued cell-cell junctions in capillary LECs, as compared to the WT littermates. Further investigation revealed that lymphatic vessels were formed in the WT mitral annulus at postnatal day 7 (P7) but not embryonic day 18.5 (E18.5). In contrast, no lymphatic vessels were found in the Fbn1 mutant mitral annulus at P7. These results suggest that the increased TGFβ signaling pathway due to the Fbn1 mutation leads to hypoplasia of lymphatic vessels in the mouse mitral valve, which may affect the lymphatic function and therefore be a cause of the mitral valve prolapse. Further studies are underway to determine the lymphatic functions in Fbn1 mutant mitral valve as well as to analyze the lymphatic vessels in human myxomatous degenerated mitral valve samples.