Abstract 14611: Phenotypic Modulation of Smooth Muscle Cells and Related Inflammation in the Development of Experimental Obstructive Pulmonary Vasculopathy in Rats
Background: We tested the hypothesis that phenotypically modulated immature smooth muscle cells (SMCs), in concert with inflammatory cells, are temporally and/ or topologically associated with the progression of occlusive pulmonary vascular diseases (PVD) in a rat model.
Methods: Pulmonary hypertension (PH) was induced by combined exposure to the vascular endothelial growth factor receptor tyrosine kinase inhibitor Sugen 5416 (20mg/kg, sc) and hypobaric hypoxia for 3 weeks in rats, which were kept in ambient air for an additional ≤10 weeks. Hemodynamic, morphometric, and immunohistochemical studies, and gene expression analyses, by using real time RT-PCR, were performed at 3, 5, 8, and 13 weeks after the initial treatment (n=78). Immunophenotyping of SMCs was performed by the combined use of SMC actin markers (α-SM actin, HHF35, CGA7) and SMC myosin heavy chain markers (SM1, SM2).
Results: Experimental animals developed PH and right ventricular hypertrophy, and exhibited a progressive increase in indices of PVD, including cellular intimal thickening, intimal fibrosis, and plexiform lesions. Cellular Intimal lesions comprised a spectrum of α-SM actin+,SM1+,SM2+/-,HHF35+,CGA7+/-,vimentin+ phenotypically modulated immature SMCs and α-SM actin+,SM1+,SM2+,HHF35+,CGA7+,vimentin+- mature SMCs in the subendothelial space. Plexiform lesions comprised α-SM actin+,SM1-,SM2-,vimentin+ myofibroblasts in the subendothelial space. Immature SMC-rich intimal lesions and plexiform lesions were proliferative (PCNA+) and infiltrated by macrophages. Fibrous intimal lesions typically included mature SMCs with a less proliferative property, and few macrophages. Compared with controls, the number of perivascular macrophages was progressively increased, and gene expression of IL6, MCP1, MMPs 2 and 9, and cathepsin-S was upregulated in the lungs in this model during the experimental period, while expression of RANTES was progressively upregulated later. IL6, MCP1, and MMP2 were expressed in intimal SMCs, while cathepsin-S and RANTES were expressed in perivascular inflammatory cells.
Conclusions: Phenotypic modulation of SMCs and related inflammation are associated with the progression of the experimental obstructive PVD in this model.
- © 2013 by American Heart Association, Inc.