Abstract 18661: Regulation of Lymphatic Physiology by Connexin47
Introduction: Mutations in GJC2, which encodes connexin47 (Cx47), are associated with lymphedema. Moreover, Cx47 mRNA was recently found in human lymphatic endothelial cells (LECs).
Hypothesis: Lymphatic endothelial Cx47 has a role in lymphatic physiology and pathology.
Methods: Confocal microscopy and qPCRs were used to assess expression of Cx47. Lymphatic drainage was studied by subcutaneous Evans Blue injections in the footpad of 12 week-old ApoE-/- or Cx47eGFP/eGFPApoE-/- mice. Atherosclerosis was studied in 15 months-old ApoE-/- or Cx47eGFP/eGFPApoE-/-mice.
Results: Cx47 was expressed in lymphangions of mesenteric collecting vessels in Cx47eGFP/eGFPProx1-mOrange2 mice as assessed by microscopy and its expression was confirmed by qPCR on mesentery, gut and skin mRNA of ApoE-/- but not Cx47eGFP/eGFPApoE-/- mice. Interestingly, lymphatic drainage was enhanced in Cx47-deficient mice (n=10/11, p<0.05). To address whether Cx47 affects chronic immuno-inflammatory pathology atherosclerotic plaque formation was studied in 15-month old male ApoE-/- and Cx47eGFP/eGFPApoE-/- mice on regular chow. These studies showed that Cx47-deficiency does not affect the size or composition (e.g. lipid, collagen or macrophage content) of aortic plaques in the aortic root. However, plaque development in the thoracic-abdominal aorta of 15 months-old mice tended to be larger in Cx47eGFP/eGFPApoE-/- mice (21±5 vs 30±4 % lipid area, n=10, p=0.08). Unexpectedly, total cholesterol (TC) and LDL, but not HDL, triglycerides or free fatty acids, were increased in serum of Cx47eGFP/eGFPApoE-/- mice as compared to ApoE-/- serum (TC: 472±24 vs 647±18 mg/dL, n=10, p<0.01; and LDL: 272±20 vs 443±17 mg/dL, n=10, p<0.001, respectively). Increased lymphatic drainage from plaques in Cx47eGFP/eGFPApoE-/- mice may, partially, compensate for increased serum TC and LDL thereby preventing exuberant atherosclerotic plaque formation despite increased serum lipid levels.
Conclusions: In conclusion, Cx47 is expressed in LECs of the lymphangion and seems implicated in multiple aspects of lymphatic (patho)physiology.
Author Disclosures: M.J. Meens: None. I. Kutkut: None. A. Sabine: None. T.V. Petrova: None. B.R. Kwak: None.
- © 2015 by American Heart Association, Inc.