Angiogenesis is an essential process in pulmonary morphogenesis. Vascular disruption can lead to alveolar abnormalities that are often fatal, such as Bronchopulmonary Dysplasia (BPD) found in premature infants. BPD studies in humans and animal models demonstrate a direct link between lung hypoplasia and impaired expression and signaling of the essential vascular mediator Vascular Endothelial Growth Factor (VEGF) and its receptors (VEGFR). Therapy using VEGF monotherapy is insufficient to rescue lung morphogenesis, as downstream VEGF signaling remains disrupted. Identifying regulators of VEGFR signaling is crucial to develop new therapeutic strategies for BPD. We recently made numerous discoveries indicating that the potent anti-angiogenic protein and proinflammatory mediator Endothelial-Monocyte Activating Polypeptide (EMAP) II functions as a likely director of pulmonary vascular formation in the developing lung as: A) its pulmonary expression is inversely correlated to periods of vascularization, B) our preliminary data indicates that EMAP II expression is markedly elevated in pulmonary epithelium and macrophages in human and animal models of BPD, and C) delivery of exogenous EMAP II profoundly disrupts alveolar-capillary growth while our preliminary data indicates that an EMAP II function blocking antibody rescues distal alveolar growth. Mechanistically, we demonstrated that EMAP II inhibits endothelial cell adhesion via ?5?1 integrin, and blocks vascular endothelial growth factor receptor II (VEGFR2) signaling. Although the mechanism by which EMAP II regulates VEGFR2 signaling is unknown, recent work suggests that EMAP II modulates the TGF receptor by targeting it for ubiquitination and degradation via SMURF2 (Smad specific ubiquitin regulatory factor 2). In addition to EMAP II's anti-angiogenic properties, EMAP II also promotes proinflammatory responses via stimulation of macrophage migration and TNF? secretion. We hypothesize that elevated expression of EMAP II in BPD results in inhibition of vascular development through a SMURF2 / VEGFR2 dependent manner that results in suppression of distal alveolar development.
Our specific aims are to: 1) determine the contribution of epithelial and macrophage EMAP II to vascular inhibition in BPD; 2) determine if EMAP II anti-angiogenic inhibition is a VEGFR2 / SMURF2 mediated mechanism; and 3) determine therapeutic potential for aerosolized delivery of an EMAP II function blocking antibody in rescuing blood vessel formation in BPD. Successful accomplishment of our specific aims will establish the scientific evidence supporting EMAP II's role in BPD and allow design of a multi-drug therapeutic approach that will enhance pulmonary vascularization. Furthermore, EMAP II's marked elevation in BPD may identify its expression as a measurable risk factor allowing it to serve as a prognostic indicator in premature infants.

Public Health Relevance

Tragically, following premature birth, the ensuing pulmonary fibrosis is often a debilitating and frequently fatal consequence of Bronchopulmonary Dysplasia (BPD). Despite advances in clinical ventilator management, the introduction of surfactant, and antenatal glucocorticoids, there is a marked lack of adjunctive therapies. Successful accomplishment of our specific aims will establish the scientific evidence supporting EMAP II's role in BPD and allow design of a multi-drug therapeutic approach that will enhance pulmonary growth in the premature infant.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL114977-05
Application #
8889718
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Xiao, Lei
Project Start
2012-09-01
Project End
2017-06-30
Budget Start
2015-07-01
Budget End
2017-06-30
Support Year
5
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Pediatrics
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Schwarz, Margaret A; Lee, Daniel D; Bartlett, Seamus (2018) Aminoacyl tRNA synthetase complex interacting multifunctional protein 1 simultaneously binds Glutamyl-Prolyl-tRNA synthetase and scaffold protein aminoacyl tRNA synthetase complex interacting multifunctional protein 3 of the multi-tRNA synthetase complex. Int J Biochem Cell Biol 99:197-202
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Awasthi, Niranjan; Hinz, Stefan; Brekken, Rolf A et al. (2015) Nintedanib, a triple angiokinase inhibitor, enhances cytotoxic therapy response in pancreatic cancer. Cancer Lett 358:59-66
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
Lee, Daniel D; Schwarz, Margaret A (2015) Adapted approach to profile genes while reconciling Vegf-a mRNA expression in the developing and injured lung. Am J Physiol Lung Cell Mol Physiol 308:L1202-11

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