Dissertation/Thesis Abstract

Midkine (MK) Regulates Pulmonary Vascular Remodeling During Hypoxia
by Reynolds, Paul R., Ph.D., University of Cincinnati, 2004, 160; 10857193
Abstract (Summary)

Midkine (MK) is a 13 kDa heparin-binding growth and differentiation factor. Immunohistochemistry revealed that MK is expressed in a precise temporal-spatial pattern during lung morphogenesis, however, its role in pulmonary homeostasis is unknown. MK staining in the respiratory epithelial cells correlated with sites of expression of thyroid transcription factor 1 (TTF-1), a transcription factor regulating formation and gene expression in the lung. Increased MK staining and mRNA expression were observed in the lungs of hypoxia-susceptible CAST/eiJ mice during hypoxia and MK expression was induced by hypoxia in vitro. We tested whether the modulator of cellular responses to hypoxia, hypoxia inducible factor-1α (HIF-1α), mediated the increase in MK expression. HIF-1α enhanced the transcription of MK, acting on HIF-1α response elements (HREs). Mutation of the 3' HRE blocked the stimulatory effects of HIF-1α. In order to directly assess the role of MK on lung morphogenesis, transgenic mice were generated which express MK in the respiratory epithelium of the developing lung. MK increased muscularization of small pulmonary arteries, increasing α-smooth muscle actin (α-SMA) and caldesmon staining and the expression of myocardin. MK directly enhanced the expression of myocardin and smooth muscle specific genes in vascular smooth muscle precursor cells. These data provide a model wherein the respiratory epithelium responds to hypoxia via HIF-1α-dependent regulation of MK. Furthermore, MK acts as a paracrine factor that enhances myocardin expression in order to influence the activation of pulmonary vascular genes.

Indexing (document details)
Advisor: Whitsett, Jeffery
School: University of Cincinnati
Department: Medicine : Molecular and Developmental Biology
School Location: United States -- Ohio
Source: DAI-B 79/10(E), Dissertation Abstracts International
Subjects: Molecular biology
Keywords: Hypoxia, Midkine, Pulmonary, Remodeling, Vascular
Publication Number: 10857193
ISBN: 978-0-438-02298-0
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