The pulmonary vascular tree has a unique design that optimizes the distribution of blood flow for gas exchange. Under normal conditions, its geometry is an end product of fetal development and postnatal growth. In disease, further restructuring occurs through vascular remodeling. Recent advances in molecular and cellular biology provide insights into how these three determinants influence vascular structure at the cellular level. The proposed work integrates physiologic studies with in situ cellular and molecular techniques to determine the functional significance of these factors in the whole living animal.
Specific aim 1 : Determine the degree of genetic control on pulmonary vascular tree growth during fetal development and how its geometry changes with postnatal growth. We will use armadillos, a unique animal that produces litters of identical offspring. By comparing the spatial distribution of blood flow within and across litters, we can quantify the genetic influence on vascular tree development and regional perfusion. We will also measure regional blood flow in growing pigs to identify patterns of blood flow redistribution. Patterns that are spatially clustered will provide evidence that postnatal growth of the pulmonary vascular tree may be locally regulated.
Specific aim 2 : Identify triggers of pulmonary vascular remodeling during chronic hypoxia. We will focus on the roles of mechanical wall stresses in promoting cellular proliferation and apoptosis in rat pulmonary arteries.
Specific aim 3 : Identify triggers of pulmonary vascular remodeling in pulmonary hypertension induced by vascular endothelial growth factor receptor-1 inhibition. We will focus on the roles of mechanical wall stresses in promoting plexiform lesions that are characteristic of primary pulmonary hypertension. The proposed work is designed to determine relationships between function, structure and genetic controls in the pulmonary circulation at the organ level. The most novel and significant aspect of the work is that cellular and molecular mechanisms will be explored in the intact animal. The findings will fill important gaps in our knowledge of pulmonary vascular development and triggers of remodeling.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL056239-04A1
Application #
6542764
Study Section
Respiratory Physiology Study Section (RESP)
Program Officer
Berberich, Mary Anne
Project Start
1997-08-20
Project End
2006-06-30
Budget Start
2002-07-01
Budget End
2003-06-30
Support Year
4
Fiscal Year
2002
Total Cost
$252,400
Indirect Cost
Name
University of Washington
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
135646524
City
Seattle
State
WA
Country
United States
Zip Code
98195
Glenny, Robb; Bernard, Susan; Neradilek, Blazej et al. (2007) Quantifying the genetic influence on mammalian vascular tree structure. Proc Natl Acad Sci U S A 104:6858-63
Gharib, Sina A; Luchtel, Daniel L; Madtes, David K et al. (2005) Global gene annotation analysis and transcriptional profiling identify key biological modules in hypoxic pulmonary hypertension. Physiol Genomics 22:14-23
Gerbino, A J; Altemeier, W A; Schimmel, C et al. (2001) Endotoxemia increases relative perfusion to dorsal-caudal lung regions. J Appl Physiol 90:1508-15
Gerbino, A J; McKinney, S; Glenny, R W (2000) Correlation between ventilation and perfusion determines VA/Q heterogeneity in endotoxemia. J Appl Physiol 88:1933-42