Matrix GLA protein, an inhibitory morphogen in pulmonary vascular development.
Deficiency of matrix GLA protein (MGP), an inhibitor of bone morphogenetic protein (BMP)-2/4, is known to cause arterial calcification and peripheral pulmonary artery stenosis. Yet the vascular role of MGP remains poorly understood. To further investigate MGP, we created a new MGP transgenic mouse model with high expression of the transgene in the lungs. The excess MGP led to a disruption of the pulmonary pattern of BMP-4, and resulted in significant morphological defects in the pulmonary artery tree. Specifically, the vascular branching pattern lacked characteristic side branching, whereas control lungs had extensive side branching accounting for as much as 40% of the vascular endothelium. The vascular changes could be explained by a dramatic reduction of phosphorylated SMAD1/5/8 in the alveolar epithelium, and in epithelial expression of the activin-like kinase receptor 1 and vascular endothelial growth factor, both critical in vascular formation. Abnormalities were also found in the terminal airways and in lung cell differentiation; high levels of surfactant protein-B were distributed in an abnormal pattern suggesting lost coordination between vasculature and airways. Ex vivo, lung cells from MGP transgenic mice showed higher proliferation, in particular surfactant protein B-expressing cells, and conditioned medium from these cells poorly supported in vitro angiogenesis compared with normal lung cells. The vascular branching defect can be mechanistically explained by a computational model based on activator/inhibitor reaction-diffusion dynamics, where BMP-4 and MGP are considered as an activating and inhibitory morphogen, respectively, suggesting that morphogen interactions are important for vascular branching.
Division of Cardiology, David Geffen School of Medicine, UCLA, Los Angeles, California 90095-1679.
Yucheng
Y
Yao
Sarah
S
Nowak
Arik
A
Yochelis
Alan
A
Garfinkel
Kristina I
KI
Boström
D000818:Animals; D001158:Arteries / Q000473:pathology; D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D003251:Constriction, Pathologic / Q000378:metabolism; D016326:Extracellular Matrix Proteins / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D008168:Lung / Q000098:blood supply / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D011650:Pulmonary Alveoli / Q000378:metabolism; D011652:Pulmonary Circulation; D037701:Pulmonary Surfactant-Associated Protein B / Q000378:metabolism; D014652:Vascular Diseases / Q000378:metabolism; D000097568:Matrix Gla Protein
D055415:Bone Morphogenetic Protein 4; D019485:Bone Morphogenetic Proteins; D002135:Calcium-Binding Proteins; D016326:Extracellular Matrix Proteins; D037701:Pulmonary Surfactant-Associated Protein B; D000097568:Matrix Gla Protein; C525809:BMP4 protein, human; C525810:Bmp4 protein, mouse