Neovascularization is a key regulatory process in fetal growth and development. Alterations within this process can lead to concomitant vascular and tissue abnormalities identified within lung dysplasia such as Bronchopulmonary Dysplasia (BPD). Although a significant amount of information exist regarding the pathologic progression of dysplastic lung diseases, little is known regarding the molecular mechanisms that regulate their formation. The goal of this proposal is to establish, whether the vasculature is a determinant of normal distal lung morphogenesis. We are optimally suited to determine the factors regulating this relationship based on our previous findings that: 1) the anti-angiogenic protein Endothelial-Monocyte Activating Polypeptide (EMAP) II is a director of neovascularization in the developing lung as its expression is inversely correlated to periods of vascularization, 2) introduction of recombinant EMAP II in a murine allograft model of lung development profoundly disrupts alveolar-capillary growth, 3) our fetal lung allograft model can examine neovascular and morphogenic relationships without placental barriers, 4) EphrinB2taulacZ and EphB4taulacZ transgenic mice can designate arterial versus venous vascular systems, and 5) fetal lung endothelial cells from TIE2gfp transgenic mice are readily isolated. We chose four strategies to identify the fundamental components of distal lung morphogenesis regulated by neovascularization, but may also be potential regulators of angiogenesis: 1) track arterial and venous progression in relationship to lung development, 2) characterize the signals sent by the fetal lung endothelium throughout lung development, 3) determine the impact that epithelial differentiation has on neovascularization, and 4) examine the contribution of the vasculature to epithelial mesenchymal structural organization. Thus, identifying the factors responsible for coordinating vascular formation and distal lung morphogenesis will provide insight into the determinants by which their balance can affect lung development.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL075764-04
Application #
7118232
Study Section
Special Emphasis Panel (ZHL1-CSR-K (S1))
Program Officer
Berberich, Mary Anne
Project Start
2003-09-30
Project End
2007-07-15
Budget Start
2006-09-01
Budget End
2007-07-15
Support Year
4
Fiscal Year
2006
Total Cost
$230,121
Indirect Cost
Name
University of Medicine & Dentistry of NJ
Department
Surgery
Type
Schools of Medicine
DUNS #
617022384
City
Piscataway
State
NJ
Country
United States
Zip Code
08854
Legan, Susan K; Lee, Daniel D; Schwarz, Margaret A (2017) ?5?1 integrin mediates pulmonary epithelial cyst formation. Dev Dyn 246:475-484
Yuan, Chujun; Yan, Lin; Solanki, Pallavi et al. (2015) Blockade of EMAP II protects cardiac function after chronic myocardial infarction by inducing angiogenesis. J Mol Cell Cardiol 79:224-31
Bennett, Katherine M; Afanador, Maria D; Lal, Charitharth V et al. (2013) Ephrin-B2 reverse signaling increases ?5?1 integrin-mediated fibronectin deposition and reduces distal lung compliance. Am J Respir Cell Mol Biol 49:680-7
Schwarz, Margaret A; Thornton, Janet; Xu, Haiming et al. (2012) Cell proliferation and migration are modulated by Cdk-1-phosphorylated endothelial-monocyte activating polypeptide II. PLoS One 7:e33101
Chen, Yao; Legan, Susan K; Mahan, Anne et al. (2012) Endothelial-monocyte activating polypeptide II disrupts alveolar epithelial type II to type I cell transdifferentiation. Respir Res 13:1
Schwarz, Margaret A; Zheng, Haihua; Legan, Susan et al. (2011) Lung self-assembly is modulated by tissue surface tensions. Am J Respir Cell Mol Biol 44:682-91
Yu, Shibin; Poe, Bryan; Schwarz, Margaret et al. (2010) Fetal and postnatal lung defects reveal a novel and required role for Fgf8 in lung development. Dev Biol 347:92-108
Schwarz, Margaret A; Caldwell, Lauren; Cafasso, Danielle et al. (2009) Emerging pulmonary vasculature lacks fate specification. Am J Physiol Lung Cell Mol Physiol 296:L71-81
Liu, Jie; Schwarz, Margaret A (2006) Identification of protease-sensitive sites in Human Endothelial-Monocyte Activating Polypeptide II protein. Exp Cell Res 312:2231-7
Schwarz, Margaret A; Zheng, Hiahua; Liu, Jie et al. (2005) Endothelial-monocyte activating polypeptide II alters fibronectin based endothelial cell adhesion and matrix assembly via alpha5 beta1 integrin. Exp Cell Res 311:229-39