This project replaces the R01 grant: """"""""VEGF protects against pulmonary vascular remodeling"""""""". Endothelial cell (EC) dysfunction plays an important role in the development of severe pulmonary hypertension (SPH). We have proposed that one of the most characteristic cellular features of SPH is the finding of EC clusters (tumorlets) in medium-size pulmonary arteries. Since these proliferated ECs express markers of angiogenesis, we have postulated that this EC growth occurs due to disordered angiogenesis. The VEGF receptor 2 (VEGFR-2) regulates several fundamental properties of ECs that impact on EC survival and nitric oxide and prostacyclin. We hypothesize that VEGF has a central role in the maintenance of the pulmonary endothelium. In this revised proposal, we seek to demonstrate that the blockade of the VEGFR-2 in combination with chronic hypoxia or monocrotaline causes severe pulmonary hypertension. We postulate that the combination of VEGFR-2 blockade and chronic hypoxia promotes death of normal pulmonary ECs and the selection of an abnormal, apoptosis-resistant, proliferating EC. Our experimental approach is based on in vivo studies with mice and rats with hypoxia- and monocrotaline-induced pulmonary hypertension (PH), ex vivo, in isolated perfused rat lungs, and, in vitro, using endothelial and lung smooth muscle cell cultures. Specifically, we propose to answer whether: 1. VEGF receptor blockade with SU5416 or ZK202650 in rats exposed to normoxia, or chronic hypoxia, or monocrotaline causes severe pulmonary hypertension associated with EC proliferation; and 2. The combination of VEGF receptor 2 blockade and chronic hypoxia leads to EC injury and EC death prior to the development of EC proliferation and SPH. Since we have successfully completed many of the originally planned experiments, we now propose experiments to confirm the specificity of our findings with SU5416 with a second, chemically unrelated VEGF receptor blocker, ZK202650, and we further probe the impact of abnormal VEGF/VEGF receptor signaling in the development of pulmonary hypertension in the transgenic mice expressing only the 188 amino-acid form of VEGF(VEGF188/188 mice) (Aim 1). In addition, we develop a novel approach to test whether apoptosis of normal lung ECs induces an apoptosis-resistant EC and SPH (Aim 2). This rodent model shares several of the key cellular and molecular features with human SPH. This proposal will allow us to better understand the natural history of human SPH associated with EC proliferation (secondary PH, project I and how alterations in pulmonary EC function affect pulmonary vascular tone and VSMC growth and hypertrophy.
| 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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