Cell Adhesion Mediated by VCAM-ITGα9 Interactions Enables Lymphatic Development.
OBJECTIVE
Adhesive ligand-receptor interactions play key roles in blood vessel angiogenesis but remain poorly characterized during lymphatic vessel growth. In this study, we use genetic approaches in both fish and mice to address the roles of cell surface integrin ligand vascular cell adhesion molecule (VCAM) and its 2 receptors, integrins α9 and α4, during lymphatic vascular development.


RESULTS
Conditional deletion of the Vcam gene was used to test VCAM function in lymphatic growth in midgestation mice. Morpholino knockdown and cRNA rescue of the 2 zebrafish vcam alleles, as well as integrins α9 and 4, were used to test the role of these ligands and receptors during lymphatic growth in the developing fish. We show that VCAM is essential for lymphatic development in the zebrafish embryo and that integrin α9 (Itgα9) rather than Itgα4 is the required VCAM receptor in the developing fish. VCAM is expressed along lines of lymphatic migration in the mouse intestine, but its loss only retards lymphatic growth.


CONCLUSIONS
These studies reveal an unexpected role for cell-cell adhesion mediated by Itgα9-VCAM interactions during lymphatic development in the fish but not in the mouse. We propose that the relative importance of cellular adhesive ligands is magnified under conditions of rapid tissue growth when the cell number increases faster than cell matrix, such as in the early zebrafish embryo.
From the Department of Medicine and Cardiovascular Institute (Y.Y., D.E., H.Z., S.C., J.Y., M.C., V.D., M.L.K.) and Department of Dermatology (D.E.), University of Pennsylvania, Philadelphia; and Department of Medicine, University of Washington, Seattle (T.P.).
Yiqing
Y
Yang
From the Department of Medicine and Cardiovascular Institute (Y.Y., D.E., H.Z., S.C., J.Y., M.C., V.D., M.L.K.) and Department of Dermatology (D.E.), University of Pennsylvania, Philadelphia; and Department of Medicine, University of Washington, Seattle (T.P.).
David
D
Enis
From the Department of Medicine and Cardiovascular Institute (Y.Y., D.E., H.Z., S.C., J.Y., M.C., V.D., M.L.K.) and Department of Dermatology (D.E.), University of Pennsylvania, Philadelphia; and Department of Medicine, University of Washington, Seattle (T.P.).
Hui
H
Zheng
From the Department of Medicine and Cardiovascular Institute (Y.Y., D.E., H.Z., S.C., J.Y., M.C., V.D., M.L.K.) and Department of Dermatology (D.E.), University of Pennsylvania, Philadelphia; and Department of Medicine, University of Washington, Seattle (T.P.).
Stephanie
S
Chia
From the Department of Medicine and Cardiovascular Institute (Y.Y., D.E., H.Z., S.C., J.Y., M.C., V.D., M.L.K.) and Department of Dermatology (D.E.), University of Pennsylvania, Philadelphia; and Department of Medicine, University of Washington, Seattle (T.P.).
Jisheng
J
Yang
From the Department of Medicine and Cardiovascular Institute (Y.Y., D.E., H.Z., S.C., J.Y., M.C., V.D., M.L.K.) and Department of Dermatology (D.E.), University of Pennsylvania, Philadelphia; and Department of Medicine, University of Washington, Seattle (T.P.).
Mei
M
Chen
From the Department of Medicine and Cardiovascular Institute (Y.Y., D.E., H.Z., S.C., J.Y., M.C., V.D., M.L.K.) and Department of Dermatology (D.E.), University of Pennsylvania, Philadelphia; and Department of Medicine, University of Washington, Seattle (T.P.).
Veerpal
V
Dhillon
From the Department of Medicine and Cardiovascular Institute (Y.Y., D.E., H.Z., S.C., J.Y., M.C., V.D., M.L.K.) and Department of Dermatology (D.E.), University of Pennsylvania, Philadelphia; and Department of Medicine, University of Washington, Seattle (T.P.).
Thalia
T
Papayannapoulou
From the Department of Medicine and Cardiovascular Institute (Y.Y., D.E., H.Z., S.C., J.Y., M.C., V.D., M.L.K.) and Department of Dermatology (D.E.), University of Pennsylvania, Philadelphia; and Department of Medicine, University of Washington, Seattle (T.P.). markkahn@mail.med.upenn.edu.
Mark L
ML
Kahn
D000818:Animals; D002448:Cell Adhesion / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000378:metabolism / Q000502:physiology; D005260:Female; D006801:Humans; D039041:Integrin alpha4beta1 / Q000378:metabolism*; D042583:Lymphangiogenesis / Q000502:physiology; D042601:Lymphatic Vessels / Q000196:embryology*; D051379:Mice; D011247:Pregnancy; D011270:Pregnancy, Animal; D013045:Species Specificity; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism*; D015027:Zebrafish
D039041:Integrin alpha4beta1; D019010:Vascular Cell Adhesion Molecule-1
cell adhesion molecules; growth and development; lymphatic vessels