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Definitive Evidence of Fundamental and Inherent Alteration in the Phenotype of Primary Pulmonary Hypertension Endothelial Cells in Angiogenesis* FREE TO VIEW

Fares A. Masri, PhD; Bela Anand-Apte, PhD; Amit Vasanji, PhD; Weiling Xu, MD; Tannishia Goggans, BS; Judith Drazba, PhD; Serpil C. Erzurum, MD, FCCP
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*From the Departments of Pulmonary and Critical Care Medicine, Cancer Biology, and Ophthalmic Research, Cole Eye Institute; and Imaging Core, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH.

Correspondence to: Serpil C. Erzurum, MD, FCCP, Cleveland Clinic Foundation, Department of Pulmonary and Critical Care Medicine, 9500 Euclid Ave/Desk A90, Cleveland, OH; e-mail: erzurus@ccf.org

Chest. 2005;128(6_suppl):571S. doi:10.1378/chest.128.6_suppl.571S-a
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Primary pulmonary hypertension (PPH) is a fatal disease characterized by a progressive increase in pulmonary artery pressure and vascular growth. Angiogenesis is the process in which new blood vessels grow from preexisting ones, with steps involving dissolution of basement membrane, endothelial cell migration, adhesion, proliferation, and tube formation. We hypothesized that pathogenesis of PPH stems from abnormalities of endothelial cells in angiogenesis. To test this, we isolated and characterized primary pulmonary artery endothelial cells (PAECs) from control and PPH lungs. In the absence of growth factors, PPH PAECs have proliferation that is fourfold greater than that of control subjects (p < 0.001), and growth factor-stimulated proliferation is threefold greater in PPH patients as compared to control subjects. Vascular endothelial growth factor increases migration in all cells, but PPH patients have an approximately twofold greater migration than control subjects in response to 10 ng/mL of vascular endothelial growth factor (p = 0.01). To evaluate angiogenesis, cells were placed on the surface of the basement membrane matrix (Matrigel; Chemicon International; Temecula, CA), and tube formation was evaluated over 2 to 24 h. Control PAECs develop an ordered pattern of endothelial cell tube formation, while PPH PAECs developed a less order branching network, with significantly thinner tube formation (n = 5; p = 0.001). Interestingly, evaluation of apoptosis by caspase 3 activity, and viability by trypan blue exclusion, revealed PPH have less apoptosis and greater viability than control cells. Our experiments reveal a fundamental alteration in the biology of PPH endothelial cells. It is unclear whether this endothelial cell behavior is part of the initiating disease process, or a repair response, but further study may contribute to understanding vascular abnormalities in PPH.

Abbreviations: PAEC = pulmonary artery endothelial cell; PPH = primary pulmonary hypertension




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