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Hypoxia inhibits human bladder smooth muscle cell proliferation: A potential mechanism of bladder dysfunction
Author(s) -
Galvin D.J.,
Watson R.W.G.,
O'Neill A.,
Coffey R.N.T.,
Taylor C.,
Gillespie J.I.,
Fitzpatrick J.M.
Publication year - 2004
Publication title -
neurourology and urodynamics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.918
H-Index - 90
eISSN - 1520-6777
pISSN - 0733-2467
DOI - 10.1002/nau.20035
Subject(s) - apoptosis , hypoxia (environmental) , cell growth , detrusor muscle , medicine , cystectomy , hyperplasia , propidium iodide , cell cycle , cell , flow cytometry , urinary bladder , andrology , cancer research , programmed cell death , endocrinology , pathology , bladder cancer , chemistry , immunology , biochemistry , organic chemistry , cancer , oxygen
Aims Recent animal studies have suggested that bladder outflow obstruction causes bladder wall hypoxia during both the filling and the voiding phases of the micturition cycle. We have previously demonstrated that mechanical deformation of human detrusor leads to smooth muscle (SM) cell hypertrophy and hyperplasia, which may then contribute to hypoxia in the dysfunctional bladder. We hypothesise that the detrusor's response to a hypoxic environment contributes to bladder dysfunction. The aim of this study was to evaluate the effect of hypoxia on detrusor cell survival and growth. Methods Normal human detrusor muscle was obtained at radical cystectomy and primary cultures were established. Cells were then cultured in the presence of 1% oxygen in a hypoxic chamber for different times. Apoptosis was assessed by propidium iodide DNA staining and flow cytometry. Proliferation was assessed by radiolabelled thymidine incorporation. Cell supernatants were retained for growth factor estimation by enzyme linked immuno‐sorbent assay (ELISA), and total cell and nuclear extracts were isolated for Western blotting. Results SM cells responded to the presence of hypoxia through significant upregulation of survival factors hypoxia inducible factor (HIF 1α) and vascular endothelial growth factor (VEGF) in a time‐dependent manner. Hypoxia did not induce cell death, but significantly reduced the rate of proliferation over time, associated with an increase in the cell cycle inhibitor p27 kip1 . Conclusions In an in vitro human detrusor cell culture model, cells demonstrate a resistance to hypoxia‐induced apoptosis but proliferation is inhibited. We suggest that the anti‐proliferative effects of hypoxia may limit the ability of detrusor cells to respond to, and compensate for, alterations in their environment contributing to bladder dysfunction. © 2004 Wiley‐Liss, Inc.