Disrupted pulmonary vascular development and pulmonary hypertension in transgenic mice overexpressing transforming growth factor-α

Abstract

Disrupted pulmonary vascular development and pulmonary hypertension in transgenic mice overexpressing transforming growth factor-␣.

Mig-6is required for appropriate lung development and to ensure normal adult lung homeostasis

“…-/-mouse lungs The morphological changes of the Mig-6 -/-mouse lungs are highly consistent with those exhibited by transgenic mice in which TGFα is overexpressed perinatally (Korfhagen et al, 1994;Kramer et al, 2007;Le Cras et al, 2004;Le Cras et al, 2003). Therefore, we examined whether Mig-6 regulates lung development through the modulation of EGF signaling.…”

“…The under-vascularization of the Mig-6 -/-lungs was detected as early as E15.5, suggesting that the vascularization defect is not a secondary change that occurs with a lung defect in newborns. In addition to the effect of angiogenetic factors, increased EGF signaling might partially contribute to the pulmonary vascular defects, as was concluded for transgenic mice expressing TGFα from the SP-C promoter (Le Cras et al, 2003). EGF signaling normally promotes angiogenesis in tumors (Goldman et al, 1993;Salomon et al, 1995); however, in developing organs, EGF might act differently given that EGF/TGFα treatment has been shown to abrogate the angiopoietic and hemangiopoietic potentials of the splanchnopleural mesoderm of avian embryos (Pardanaud and Dieterlen-Lievre, 1999).…”

“…Overexpression of TGFα, an EGFR ligand, in the perinatal lung disrupts alveolarization and vascularization, leading to lung fibrosis in the adult (Korfhagen et al, 1994;Kramer et al, 2007;Le Cras et al, 2004;Le Cras et al, 2003). EGF can also activate the downstream signaling pathways RAS-PI3K/AKT and RAS/MAPK (Copland and Post, 2007;Kling et al, 2006;Uzumcu et al, 2002;Wang et al, 2005), and can cross-talk with other growth factors, such as TGFβ1 (Ding et al, 2007) and human growth hormone (HGF) signaling (Chess et al, 1998), all of which are important for lung development.…”

Genomic Profile of Matrix and Vasculature Remodeling in TGF-α–Induced Pulmonary Fibrosis

“…RVH was assessed as previously described (22). Briefly, hearts were removed and dissected to isolate the free wall of the RV from the left ventricle and septum (LV 1 S).…”

Characterization of agonist-induced vasoconstriction in mouse pulmonary artery

“…With respect to pulmonary hypertension, transgenic or knockout mouse models have been developed to evaluate the modulation of pulmonary vasoconstriction and remodeling due to 1) endothelial nitric oxide synthase disruption (18,47,57); 2) vasoactive and mitogenic agonists, such as hypoxia-inducible factors-1␣ (63) and -2␣ (2), calcitonin gene-related peptide (5), serotonin (5-HT) (9,32,34,45), matrix metalloproteinases (67), transforming growth factor-␤ (35), and vasoactive intestinal peptide (51); 3) bone morphogenetic protein receptor type II gene mutations and altered bone morphogenetic protein signaling (19,28,40,62); 4) altered function of ion channels (12) and transporters (49); and 5) altered superoxide production (36,38). Despite these studies, there is still relatively little information regarding the basic characterization of the pulmonary vascular reactivity in normal mice.…”