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.

3 Reads
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Differentiation of fibroblasts to myofibroblasts and collagen fibrillogenesis are two processes essential for normal cutaneous development and repair, but their misregulation also underlies skin-associated fibrosis. Periostin is a matricellular protein normally expressed in adult skin, but its role in skin organogenesis, incisional wound healing and skin pathology has yet to be investigated in any depth. Using C57/BL6 mouse skin as model, we first investigated periostin protein and mRNA spatiotemporal expression and distribution during development and after incisional wounding. Secondarily we assessed whether periostin is expressed in human skin pathologies, including keloid and hypertrophic scars, psoriasis and atopic dermatitis. During development, periostin is expressed in the dermis, basement membrane and hair follicles from embryonic through neonatal stages and in the dermis and hair follicle only in adult. In situ hybridization demonstrated that dermal fibroblasts and basal keratinocytes express periostin mRNA. After incisional wounding, periostin becomes re-expressed in the basement membrane within the dermal-epidermal junction at the wound edge re-establishing the embryonic deposition pattern present in the adult. Analysis of periostin expression in human pathologies demonstrated that it is over-expressed in keloid and hypertrophic scars, atopic dermatitis, but is largely absent from sites of inflammation and inflammatory conditions such as psoriasis. Furthermore, in vitro we demonstrated that periostin is a transforming growth factor beta 1 inducible gene in human dermal fibroblasts. We conclude that periostin is an important ECM component during development, in wound healing and is strongly associated with pathological skin remodeling.
    Journal of Cell Communication and Signaling 06/2010; 4(2):99-107. DOI:10.1007/s12079-010-0090-2
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Periostin (Postn) is a heterofunctional secreted extracellular matrix (ECM) protein comprised of four fasciclin domains that promotes cellular adhesion and movement, as well as collagen fibrillogenesis. Postn is expressed in unique growth centers during embryonic development where it facilitates epithelial-mesenchymal transition (EMT) of select cell populations undergoing reorganization. In the heart, Postn is expressed in the developing valves, cardiac fibroblasts and in regions of the outflow track. In the adult, Postn expression is specifically induced in areas of tissue injury or areas with ongoing cellular re-organization. In the adult heart Postn is induced in the ventricles following myocardial infarction, pressure overload stimulation, or generalized cardiomyopathy. Here we will review the functional consequences associated with Postn induction in both the developing and adult heart. The majority of data collected to date suggest a common function for Postn in both development and disease as a potent inducible regulator of cellular reorganization and extracellular matrix homeostasis, although some alternate and controversial functions have also been ascribed to Postn, the validity of which will be discussed here.
    Current Genomics 01/2009; 9(8):548-55. DOI:10.2174/138920208786847917 · 2.34 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Unraveling isolation, cultivation and transplantation protocols is often difficult and time consuming but essential to exploit the full potential of cell based therapies. Studying periosteal callus formation, may give novel insights how this tissue can be used to repair cartilage and bone defects and thus bypass optimization of the protocols mentioned above. Periosteal callus can be induced in vivo without breaking the bone. During periosteal callus formation, osteochondrogenic progenitor cells which reside in the cambium cambium layer, differentiate via the sequential steps of endochondral bone formation; chondrogenesis is initiated then chondrocytes differentiate into hypertrophic cells. These hypertrophic chondrocytes release pro-angiogenic factors, mineralize and bone is deposited. Grafts can be harvested during the chondrogenic phase. Compared to isolated undifferentiated periosteal cells, cells in these grafts survive the transplantation into an osteochondral defect much better. By injecting a gel between bone and periosteum, the micro-environment can be manipulated. Per example inhibition of vascularization and induction of hypoxia enhances periosteal chondrogenesis both in vitro and in vivo. Taken together, studying repair processes of the body in detail may not only give essential information for different cell based therapies, but can even lead to a complete other approach in which the body its own regenerative capacity is used.
    NATO Science for Peace and Security Series A: Chemistry and Biology 01/2010; DOI:10.1007/978-90-481-8790-4_5
Show more