Increased Pericyte Coverage Mediated by Endothelial-Derived Fibroblast Growth Factor-2 and Interleukin-6 Is a Source of Smooth Muscle–Like Cells in Pulmonary Hypertension

• Published in: Circulation (New York, N.Y.) Vol. 129; no. 15; pp. 1586 - 1597
• Main Authors: Ricard, Nicolas, Tu, Ly, Le Hiress, Morane, Huertas, Alice, Phan, Carole, Thuillet, Raphaël, Sattler, Caroline, Fadel, Elie, Seferian, Andrei, Montani, David, Dorfmüller, Peter, Humbert, Marc, Guignabert, Christophe
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD by the American College of Cardiology Foundation and the American Heart Association, Inc 15.04.2014; Lippincott Williams & Wilkins; American Heart Association
• Subjects: Adult; Animals; Biological and medical sciences; Blood and lymphatic vessels; Cardiology and cardiovascular system; Cardiology. Vascular system; Cell Communication - drug effects; Cell Communication - physiology; Cell Differentiation - drug effects; Cell Differentiation - physiology; Cells, Cultured; Cellular Biology; Disease Models, Animal; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Endothelial Cells - cytology; Endothelial Cells - drug effects; Endothelial Cells - physiology; Female; Fibroblast Growth Factor 2 - pharmacology; Fibroblast Growth Factor 2 - physiology; Human health and pathology; Humans; Hypertension, Pulmonary - pathology; Hypertension, Pulmonary - physiopathology; Interleukin-6 - pharmacology; Interleukin-6 - physiology; Life Sciences; Male; Medical sciences; Mice; Mice, Transgenic; Microcirculation - physiology; Middle Aged; Muscle, Smooth, Vascular - cytology; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - physiology; Neovascularization, Physiologic - physiology; Pericytes - cytology; Pericytes - drug effects; Pericytes - physiology; Pneumology; Pulmonary Circulation - physiology; Pulmonary hypertension. Acute cor pulmonale. Pulmonary embolism. Pulmonary vascular diseases; Pulmonology and respiratory tract; Rats; Rats, Wistar; Retinal Vessels - cytology; Retinal Vessels - physiology; Fibroblast growth factor; Pericyte; Transforming growth factor β; transforming growth factor beta; Smooth muscle; Cardiovascular disease; Source; interleukin-6; Interleukin 6; cell communication; Blood vessel; fibroblast growth factor 2; Cardiology; Cell; pulmonary arterial hypertension; Communication; Respiratory disease; pericytes; Cytokine; Coverage; endothelilal cells; Artery; Pulmonary hypertension; Endothelium; Circulatory system
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/CIRCULATIONAHA.113.007469

BACKGROUND—Pericytes and their crosstalk with endothelial cells are critical for the development of a functional microvasculature and vascular remodeling. It is also known that pulmonary endothelial dysfunction is intertwined with the initiation and progression of pulmonary arterial hypertension (PAH). We hypothesized that pulmonary endothelial dysfunction, characterized by abnormal fibroblast growth factor-2 and interleukin-6 signaling, leads to abnormal microvascular pericyte coverage causing pulmonary arterial medial thickening. METHODS AND RESULTS—In human lung tissues, numbers of pericytes are substantially increased (up to 2-fold) in distal PAH pulmonary arteries compared with controls. Interestingly, human pulmonary pericytes exhibit, in vitro, an accentuated proliferative and migratory response to conditioned media from human idiopathic PAH endothelial cells compared with conditioned media from control cells. Importantly, by using an anti–fibroblast growth factor-2 neutralizing antibody, we attenuated these proliferative and migratory responses, whereas by using an anti–interleukin-6 neutralizing antibody, we decreased the migratory response without affecting the proliferative response. Furthermore, in our murine retinal angiogenesis model, both fibroblast growth factor-2 and interleukin-6 administration increased pericyte coverage. Finally, using idiopathic PAH human and NG2DsRedBAC mouse lung tissues, we demonstrated that this increased pericyte coverage contributes to pulmonary vascular remodeling as a source of smooth muscle–like cells. Furthermore, we found that transforming growth factor-β, in contrast to fibroblast growth factor-2 and interleukin-6, promotes human pulmonary pericyte differentiation into contractile smooth muscle–like cells. CONCLUSIONS—To the best of our knowledge, this is the first report of excessive pericyte coverage in distal pulmonary arteries in human PAH. We also show that this phenomenon is directly linked with pulmonary endothelial dysfunction.