This application aims to investigate bone marrow (BM)-derived precursor cells in the context of severe, angioproliferative pulmonary arterial hypertension (PAH, a group of nearly always lethal diseases. The incidence of pulmonary hypertension (PH) appears to be increasing, which might also be related to more frequent diagnosis due to more common use of echocardiography. PH has also been recognized as an indicator of increased mortality in patients with interstitial lung diseases. The 4th WHO conference in Dana Point updated the pathobiological concepts of severe PH, yet no curative therapy has been found so far. It is increasingly acknowledged that the cells in the angioproliferative lesions are apoptosis-resistant, and the recent years have generated substantial information about the contribution of BM-derived precursor cells to vascular remodeling, but it has not been investigated whether or not BM-derived precursor cells participate in the development of angioproliferative lesions in PAH. Our group has established the SU5416/chronic hypoxia (SuHx) model as a model of severe angioproliferative PAH. Our central hypothesis is that BM-derived precursor cells are important and contribute to the development of angioproliferative lesions via growth factor production and engraftment into the vessel wall. Our preliminary data indicate the presence of pluripotent cells in and around small pulmonary arteries in SuHx animals. In the course of the proposed experiments, we will establish various techniques, including BM reconstitution and FACS analysis as tools to elucidate the role of bone-marrow derived precursor cells in the development of angioproliferative lesions in severe experimental PAH. The hypothesis that BM-derived precursor cells contribute significantly to angioproliferation in PAH will be tested in two Specific Aims:
In Specific Aim 1, we will answer the question whether BM-derived precursor cells are increased in angioproliferative lesions and blood, and show enhanced production of growth factors, in severe, angioproliferative PAH.
In Specific Aim 2, we will investigate the mechanisms of BM-derived precursor cell recruitment into the pulmonary vasculature in severe angioproliferative PAH. We will specifically examine whether apoptosis inhibition and blocking CXCR4 will decrease precursor cell homing, angioproliferation and PH. In sum, this project aims to demonstrate that BM-derived precursor cells contribute to angioproliferation in PAH via growth factor production and engraftment into the vessel wall.

Public Health Relevance

In this proposal, we will investigate the question, whether bone marrow-derived precursor cells participate in the development of angioproliferative pulmonary arterial hypertension. This question of high translational relevance, as there is currently no curative therapy for angioproliferative PH and precursor cells are already currently investigated for therapy of PH without an understanding of the contribution of bone marrow-derived precursor cells to pulmonary arterial angioproliferation. By uncovering the mechanisms, such as local engraftment or production of angiogenic growth factors, which underlie the contribution of bone marrow- derived precursor cells, new therapeutic options may arise from inhibiting the homing of precursor cells or from using genetically modified precursor cells as vehicles for specific therapy.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21HL109918-02
Application #
8302191
Study Section
Respiratory Integrative Biology and Translational Research Study Section (RIBT)
Program Officer
Moore, Timothy M
Project Start
2011-07-15
Project End
2013-11-30
Budget Start
2012-05-01
Budget End
2013-11-30
Support Year
2
Fiscal Year
2012
Total Cost
$186,875
Indirect Cost
$61,875
Name
Virginia Commonwealth University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
105300446
City
Richmond
State
VA
Country
United States
Zip Code
23298
Farkas, Daniela; Kraskauskas, Donatas; Drake, Jennifer I et al. (2014) CXCR4 inhibition ameliorates severe obliterative pulmonary hypertension and accumulation of C-kit⁺ cells in rats. PLoS One 9:e89810