Angiogenesis, the process whereby new blood vessels sprout and emerge from an established network, has been widely investigated in most organs. Understanding the mechanisms involved is important both for therapeutic promotion of new vessel growth in ischemic tissues as well as retardation of the process in tumors. In this proposal, we utilize a unique mouse model that allows study of the signaling of both of these processes in the lungs within individual animals. The lung is unique in that angiogenesis takes place in an ischemic but hyperoxic environment and the new vasculature is from systemic (bronchial or intercostal) arteries and not the pulmonary vasculature. After lateral thoracotomy and ligation of the left pulmonary artery in the mouse, rapid new blood vessel growth results from the intercostal arteries in immediate proximity to the site of thoracotomy. Within 5-7 days, these new blood vessels invade the upper ischemic lung region but not the lower ischemic lung. Pulmonary ischemia is essential since sham thoracotomy does not result in lung angiogenesis. These observations suggest cross communication of the thoracic wall undergoing wound repair with the upper ischemic lung. Preliminary data demonstrate that the ELR+, C-X-C chemokines in both the thoracic wall and the upper ischemic lung are essential proteins participating in this cross communication. We hypothesize that pulmonary ischemia induces lung tissue proteins that stimulate nearby intercostal vessels, to proliferate and invade the ischemic lung.
Specific aims of this proposal are to determine the dynamics of chemokine synthesis in the lung and thoracic wall, with emphasis on the relative differences between the ischemic upper and lower lung regions after left pulmonary artery ligation. We will correlate the changes in chemokine expression with physiologic assessment of the magnitude and distribution of new systemic blood flow to the lung. In vitro studies assessing mouse endothelial cell proliferation and migration will be used to determine critical factors defining the proangiogenic phenotype of systemic arterial endothelial cells relative to pulmonary endothelial cells. The results of these studies will provide important new information defining the molecular, structural, and functional events of lung angiogenesis.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL071605-03
Application #
6904595
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Denholm, Elizabeth M
Project Start
2003-07-01
Project End
2008-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
3
Fiscal Year
2005
Total Cost
$408,750
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Tankersley, Clarke G; Moldobaeva, Aigul; Wagner, Elizabeth M (2012) Strain variation in response to lung ischemia: role of MMP-12. Respir Res 13:93
Moldobaeva, Aigul; van Rooijen, Nico; Wagner, Elizabeth M (2011) Effects of ischemia on lung macrophages. PLoS One 6:e26716
Eldridge, Lindsey; Moldobaeva, Aigul; Wagner, Elizabeth M (2011) Increased hyaluronan fragmentation during pulmonary ischemia. Am J Physiol Lung Cell Mol Physiol 301:L782-8
Moldobaeva, Aigul; Baek, Amy; Eldridge, Lindsey et al. (2010) Differential activity of pro-angiogenic CXC chemokines. Microvasc Res 80:18-22
Nijmeh, Julie; Moldobaeva, Aigul; Wagner, Elizabeth M (2010) Role of ROS in ischemia-induced lung angiogenesis. Am J Physiol Lung Cell Mol Physiol 299:L535-41
Moldobaeva, Aigul; Baek, Amy; Wagner, Elizabeth M (2008) MIP-2 causes differential activation of RhoA in mouse aortic versus pulmonary artery endothelial cells. Microvasc Res 75:53-8
Sukkar, Adlah; Jenkins, John; Sanchez, Jesus et al. (2008) Inhibition of CXCR2 attenuates bronchial angiogenesis in the ischemic rat lung. J Appl Physiol 104:1470-5
Sanchez, Jesus; Moldobaeva, Aigul; McClintock, Jessica et al. (2007) The role of CXCR2 in systemic neovascularization of the mouse lung. J Appl Physiol 103:594-9
Wagner, Elizabeth M; Karagulova, Gulnura; Jenkins, John et al. (2006) Changes in lung permeability after chronic pulmonary artery obstruction. J Appl Physiol 100:1224-9