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.
- [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.
- [Show abstract] [Hide abstract]
ABSTRACT: Three new software systems, Ingenuity pathway analysis(IPA, TranscriptomeBrowser and MetaCore, were compared by analyzing chondrocyte microarray data of Kashin-Beck disease (KBD) and primary knee osteoarthritis(OA) to understand the pathway or network analysis software which has a superior function to identify target genes with easy operation and effective for differential diagnosis and treatment of KBD and OA. RNA was isolated from cartilage samples taken from KBD patients and OA ones. Agilent 44K human whole genome oligonucleotide microarrays were used to detect differentially expressed genes. From IPA, we identified one significant canonical pathway and two significant networks. From GeneHub analysis, we got three networks. One significant canonical pathway and one significant network were obtained from TranscriptomeBrowser analysis. POSTN and LEF1 which were got from IPA, RAC2 which was identified by both of the IPA and TranscriptomeBrowser may be most closely related to the etiopathogenesis of KBD. According to our data analysis, IPA and TranscriptomeBrowser are suitable for pathway analysis, while, TranscriptomeBrowser is suitable for network analysis. The significant genes obtained from IPA and TranscriptomeBrowser analysis may thus provide a better understanding of the molecular details in the pathogenesis of KBD and also provide useful pathways and network maps for future research in osteochondrosis.Gene 10/2012; · 2.20 Impact Factor