Submitted on February 24, 2009
Revised on May 8, 2009
Accepted on May 8, 2009
Hindlimb Unweighting Induces Changes in the p38MAPK Contractile Pathway of the Rat Abdominal Aorta
Scott Matthew Summers1, Yuichiro Hayashi1, Steven Vu Nguyen1, Thu Minh Nguyen1, and Ralph Earl Purdy1*
1 University of California at Irvine
* To whom correspondence should be addressed. E-mail: repurdy{at}uci.edu.
Hindlimb unweighting (HLU) of rats is a model used to mimic the cephalic fluid shift potentially involved in the orthostatic intolerance experienced by astronauts. Certain arteries in these rats exhibit a decreased contractile response to adrenergic agonists. It was shown previously that this may be caused by changes in thick filament regulation (Vascul Pharm 2008;48:208-14). In the present study, it was hypothesized that HLU also modifies thin filament regulation by effects on p38MAPK and ERK. Abdominal aorta rings from 20 day HLU rats and untreated controls were subjected to phenylephrine and phorbol 12, 13-dibutyrate (PDBU) concentration response curves in the presence and absence of two inhibitors, the p38MAPK inhibitor SB203580 and the MEK inhibitor U0126. SB203580 decreased control sensitivity to both agonists, but HLU sensitivity was not significantly affected. U0126 which blocks enzymes immediately upstream of ERK affected sensitivity to both agonists equally between control and HLU. Western blotting revealed no change in total levels of p38MAPK and its downstream target, HSP27, but did reveal a decrease in phosphorylated levels of both after stimulation with PDBU and phenylephrine after HLU treatment. Neither total ERK, nor phosphorylated levels after stimulation, were affected by HLU. Total levels of caldesmon, a molecule downstream of both pathways, were decreased, but phosphorylated levels after stimulation were decreased by roughly twice as much. The results of this study demonstrate that HLU down-regulates p38MAPK, but not ERK, signaling. In turn, this may decrease actin availability for contraction.
