Circulating Angiogenic Precursors in Idiopathic Pulmonary Arterial Hypertension

• Published in: The American journal of pathology Vol. 172; no. 3; pp. 615 - 627
• Main Authors: Asosingh, Kewal, Aldred, Micheala A, Vasanji, Amit, Drazba, Judith, Sharp, Jacqueline, Farver, Carol, Comhair, Suzy A.A, Xu, Weiling, Licina, Lauren, Huang, Lan, Anand-Apte, Bela, Yoder, Mervin C, Tuder, Rubin M, Erzurum, Serpil C
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Elsevier Inc 01.03.2008; ASIP; American Society for Investigative Pathology
• Subjects: AC133 Antigen; Adult; Animals; Antigens, CD - metabolism; Antigens, CD34 - metabolism; Biological and medical sciences; Bone Marrow Cells - metabolism; Bone Marrow Cells - pathology; Bone Morphogenetic Protein 2; Bone Morphogenetic Proteins - pharmacology; Cell Movement - drug effects; Cell Proliferation - drug effects; Cells, Cultured; Endothelial Cells - metabolism; Endothelial Cells - pathology; Female; Glycoproteins - metabolism; Hematopoietic Stem Cells - metabolism; Hematopoietic Stem Cells - pathology; Humans; Hypertension, Pulmonary - blood; Hypertension, Pulmonary - pathology; Investigative techniques, diagnostic techniques (general aspects); Male; Medical sciences; Mice; Mice, Inbred NOD; Middle Aged; Pathology; Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques; Peptides - metabolism; Pneumology; Pulmonary hypertension. Acute cor pulmonale. Pulmonary embolism. Pulmonary vascular diseases; Regular; Stem Cells - metabolism; Stem Cells - pathology; Transforming Growth Factor beta - pharmacology; Angiogenesis; Anatomic pathology; Respiratory disease; Blood vessel; Idiopathic; Cardiovascular disease; Circulatory system; Neovascularization; Precursor; Artery; Pulmonary hypertension
• ISSN: 0002-9440; 1525-2191
• DOI: 10.2353/ajpath.2008.070705

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-β 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.