Chen, Y.F. et al. Atrial natriuretic peptide-dependent modulation of hypoxia-induced pulmonary vascular remodeling. Life Sci. 79, 1357-1365

Vascular Biology and Hypertension Program, Department of Medicine, Division of Cardiovascular Disease, University of Alabama at Birmingham, 35296, USA.
Life Sciences (Impact Factor: 2.7). 09/2006; 79(14):1357-65. DOI: 10.1016/j.lfs.2006.03.051
Source: PubMed


Hypoxic stress upsets the balance in the normal relationships between mitogenic and growth inhibiting pathways in lung, resulting in pulmonary vascular remodeling characterized by hyperplasia of pulmonary arterial smooth muscle cells (PASMCs) and fibroblasts and enhanced deposition of extracellular matrix. Atrial natriuretic peptide (ANP) reduces pulmonary vascular resistance and attenuates hypoxia-induced pulmonary hypertension in vivo and PASMC proliferation and collagen synthesis in vitro. The current study utilized an ANP null mouse model (Nppa-/-) to test the hypothesis that ANP modulates the pulmonary vascular and alveolar remodeling response to normobaric hypoxic stress. Nine-10 wk old male ANP null (Nppa-/-) and wild type nontransgenic (NTG) mice were exposed to chronic hypoxia (10% O(2), 1 atm) or air for 6 wks. Measurement: pulmonary hypertension, right ventricular hypertrophy, and pulmonary arterial and alveolar remodeling were assessed. Hypoxia-induced pulmonary arterial hypertrophy and muscularization were significantly increased in Nppa-/- mice compared to NTG controls. Furthermore, the stimulatory effects of hypoxia on alveolar myofibroblast transformation (8.2 and 5.4 fold increases in Nppa-/- and NTG mice, respectively) and expression of extracellular matrix molecule (including osteopontin [OPN] and periostin [PN]) mRNA in whole lung were exaggerated in Nppa-/- mice compared to NTG controls. Combined with our previous finding that ANP signaling attenuates transforming growth factor (TGF)-beta-induced expression of OPN and PN in isolated PASMCs, the current study supports the hypothesis that endogenous ANP plays an important anti-fibrogenic role in the pulmonary vascular adaptation to chronic hypoxia.

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    • "During wound repair and certain pathologies, changes occur in the composition of the matricellular ECM to provide cell–matrix signals and misregulation of the changes can result in development of various pathologies (Midwood, Valenick et al. 2004; Berk, Fujiwara et al. 2007; Darby and Hewitson 2007). Periostin is prominently expressed during pathological ECM remodeling, including in heart tissue after myocardial infarction (Kuhn et al. 2007; Shimazaki et al. 2008), asthma-associated subepithelial fibrosis in lungs (Takayama et al. 2006), and pulmonary vascular remodeling (Chen et al. 2006). We have now confirmed that periostin protein is abundant in fibrotic scars, but not in chronically inflammed skin. "
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    • "Specifically, myocardial infarction (MI) or pressure overload stimulation to the adult heart induces abundant re-expression of Postn from resident fibroblasts located between myocytes within the heart parachyma proper (Fig. 2A-C), where prior to such stimulation the major expression of Postn in the heart is within the collagen rich environment of the valves [20, 21, 45-48]. Postn expression is also induced at sites of vascular injury and hyperplasia [18, 49, 50], in the lung after injury/fibrosis [8, 51], in and around tumors [13], and at wound sites [52]. While not unequivocally proven, these various studies suggest a common biologic response whereby Postn becomes re-expressed at injury or inflammatory sites within the adult organism, often associated with a need for ECM and cellular migration, not unlike many developmental processes associated with Postn expression. "
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