This PPG application has evolved from three presently active R01 grants, which this application intends to replace. Severe chronic pulmonary hypertension (PH) - in spite of intravenous prostacyclin (PGI2) treatment - remains an important and challenging clinical problem. Our four projects have been designed to investigate specific aspects of human PH including primary and neonatal pulmonary hypertension. We start with the concept that pulmonary arteries differ from systemic vessels in that their response to """"""""stress"""""""" or """"""""injury"""""""" is different. We further postulate that the adult lung circulation remodels with endothelial cell proliferation (Project 1), whereas the neonatal lung circulation remodels without endothelial cell proliferation (Project 2). Vascular endothelial growth factor (VEGF) and its receptor, KDR. are critically involved in the formation of plexiform lesions in adult PH whereas reduced VEGF/KDR signaling in the fetus leads to a vasculogenesis failure characterized by a muscularized, pruned vascular tree. Project 3 develops a prospectively designed new rodent model of endothelial cell-proliferative, severe PH that has been built on inhibition of the VEGF receptor KDP, and proposes that endothelial cell death selects for the emergence of resistant, proliferative endothelial cells at sites of high shear stress. We anticipate that this rat model will permit the systematic investigation of the interplay between altered vasoreactivity (vasoconstriction) and development of obliterative pulmonary vascular arteriopathy. The information gathered from this model will include lung tissue transcript information gathered using the microarray GeneChip technology and will be compared with the gene expression data obtained from human PPH and 2nd PH lungs (Project 1). The fact that endothelial cell proliferation in PPH is monoclonal encourages the search for gene mutations. One candidate mutated gene is the TGF-B-RII gene coding for the TGF-B-II receptor, which is involved in cell growth/death control. Lastly, a severe loss of prostacyclin receptor (PGII-R) expression in the resistance vessels of PPH lungs provides rationale and focus for the investigation of the role of PGI2 and its receptor in pulmonary vascular remodeling (Project 4). Vascular smooth muscle cells from genetically engineered mice (Lung-specific PGI2-synthase gene overexpression and PGI2-receptor knock-out) will be examined for PGI2-R-dependent and independent growth. We believe that this highly integrated program addresses central issues of the pathobiology of severe human pulmonary hypertension.
| Sakao, Seiichiro; Tatsumi, Koichiro; Voelkel, Norbert F (2010) Reversible or irreversible remodeling in pulmonary arterial hypertension. Am J Respir Cell Mol Biol 43:629-34 |
| Sakao, Seiichiro; Tatsumi, Koichiro; Voelkel, Norbert F (2009) Endothelial cells and pulmonary arterial hypertension: apoptosis, proliferation, interaction and transdifferentiation. Respir Res 10:95 |
| Rai, Pradeep R; Cool, Carlyne D; King, Judy A C et al. (2008) The cancer paradigm of severe pulmonary arterial hypertension. Am J Respir Crit Care Med 178:558-64 |
| Taraseviciene-Stewart, Laimute; Nicolls, Mark R; Kraskauskas, Donatas et al. (2007) Absence of T cells confers increased pulmonary arterial hypertension and vascular remodeling. Am J Respir Crit Care Med 175:1280-9 |
| Tuder, Rubin M; Marecki, John C; Richter, Amy et al. (2007) Pathology of pulmonary hypertension. Clin Chest Med 28:23-42, vii |
| Sakao, Seiichiro; Taraseviciene-Stewart, Laimute; Cool, Carlyne D et al. (2007) VEGF-R blockade causes endothelial cell apoptosis, expansion of surviving CD34+ precursor cells and transdifferentiation to smooth muscle-like and neuronal-like cells. FASEB J 21:3640-52 |
| Oka, Masahiko; Homma, Noriyuki; Taraseviciene-Stewart, Laimute et al. (2007) Rho kinase-mediated vasoconstriction is important in severe occlusive pulmonary arterial hypertension in rats. Circ Res 100:923-9 |
| Sakao, Seiichiro; Taraseviciene-Stewart, Laimute; Wood, Kathy et al. (2006) Apoptosis of pulmonary microvascular endothelial cells stimulates vascular smooth muscle cell growth. Am J Physiol Lung Cell Mol Physiol 291:L362-8 |
| Taraseviciene-Stewart, Laimute; Scerbavicius, Robertas; Choe, Kang-Hyeon et al. (2006) Simvastatin causes endothelial cell apoptosis and attenuates severe pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 291:L668-76 |
| Taraseviciute, Agne; Voelkel, Norbert F (2006) Severe pulmonary hypertension in postmenopausal obese women. Eur J Med Res 11:198-202 |
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