Atrial natriuretic peptide-dependent modulation of hypoxia-induced pulmonary vascular remodeling
ABSTRACT 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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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.Summary: Periostin is a fibrogenic protein that mediates fibroblast differentiation and extracellular matrix synthesis. Here, we show that periostin is dynamically and temporally expressed during skin development, is induced by TGF-beta1 in vitro and is significantly upregulated during wound repair as well as cutaneous pathologies.Journal of Cell Communication and Signaling 06/2010; 4(2):99-107. DOI:10.1007/s12079-010-0090-2
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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