Published online before print February 7, 2008

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Copyright © 2008 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2008.070705

Accepted for publication November 29, 2007.

Article

Circulating Angiogenic Precursors in Idiopathic Pulmonary Arterial Hypertension

Kewal Asosingh^*, Micheala A. Aldred^¶, Amit Vasanji^||, Judith Drazba^||, Jacqueline Sharp^*, Carol Farver^*||, Suzy A.A. Comhair^*, Weiling Xu^*, Lauren Licina^*, Lan Huang^**, Bela Anand-Apte, Mervin C. Yoder^**, Rubin M. Tuder, and Serpil C. Erzurum^*@

From the Departments of Pathobiology,* Pulmonary, Allergy, and Critical Care Medicine, Genomic Medicine Institute, Imaging,^|| Lerner Research Institute, and the Cole Eye Institute, The Cleveland Clinic, Cleveland, Ohio; the Taussig Cancer Center and the Department of Genetics,^¶ Case Western Reserve University School of Medicine, Cleveland, Ohio; the Division of Cardiopulmonary Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland; and the Department of Pediatrics,** Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana

^@ To whom correspondence should be addressed. E-mail: erzurus{at}ccf.org.

	Abstract

Vascular remodeling in idiopathic pulmonary arterial hypertension (IPAH) involves hyperproliferative and apoptosis-resistant pulmonary artery endothelial cells. In this study, we evaluated the relative contribution of bone marrow-derived proangiogenic precursors and tissue-resident endothelial progenitors to vascular remodeling in IPAH. Levels of circulating CD34⁺CD133⁺ bone marrow-derived proangiogenic precursors were higher in peripheral blood from IPAH patients than in healthy controls and correlated with pulmonary artery pressure, whereas levels of resident endothelial progenitors in IPAH pulmonary arteries were comparable to those of healthy controls. Colony-forming units of endothelial-like cells (CFU-ECs) derived from CD34⁺CD133⁺ bone marrow precursors of IPAH patients secreted high levels of matrix metalloproteinase-2, had greater affinity for angiogenic tubes, and spontaneously formed disorganized cell clusters that increased in size in the presence of transforming growth factor- or bone morphogenetic protein-2. Subcutaneous injection of NOD SCID mice with IPAH CFU-ECs within Matrigel plugs, but not with control CFU-ECs, produced cell clusters in the Matrigel and proliferative lesions in surrounding murine tissues. Thus, mobilization of high levels of proliferative bone marrow-derived proangiogenic precursors is a characteristic of IPAH and may participate in the pulmonary vascular remodeling process.