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PhD Thesis: Scott Summers

Dissertation Abstract:
Changes in the Vascular Endothelium and Smooth Muscle Second Messenger Signaling Systems in Simulated Microgravity using the Hindlimb Unweighted Rat

By Scott Matthew Summers
Doctor of Philosophy in Pharmacology and Toxicology
University of California, Irvine, 2008
Professor Ralph E. Purdy, Chair

Chronic exposure to microgravity exerts many effects on the body. In the cardiovascular system, microgravity initiates a fluid shift towards the head which may be the cause of the orthostatic intolerance that astronauts often develop. To study the fluid shift on earth, a rat model known as hindlimb unweighting, where a rat was suspended by its tail at a 30-degree angle for 20 days, has been used. Previous work had demonstrated that certain arteries had a decreased response to some contractile agonists after HLU treatment. The present examined three different changes that occur in rat arteries after HLU and related to their response to contractile and vasorelaxing agonists.

Using organ bath responses, it was found in the HLU rat the thoracic aorta endothelium, a layer of cells involved in vasorelaxation, was actually more active. The thoracic aorta showed a greater increase in contraction after endothelium removal in the HLU than in the control and the HLU was more sensitive to both a muscarinic agonist and the nitric oxide mimetic sodium nitroprusside. In the abdominal aorta, this study showed a decrease in the activity of the Rho pathway in vascular smooth muscle through both Western blots detailing decreased total and activated proteins in the pathway and decreased functional inhibition of the Rho Kinase inhibitor Y27632 in the HLU as compared to control. 

Using organ bath responses, a decrease in the activity of the separate ERK or p38MAPK pathways could be involved in the contractile deficit of the HLU rat. To examine this, the p38MAPK inhibitor SB203580 was used, and showed significantly less of an effect in HLU compared to the control against the stimulants Phorbol 12, 13 dibutyrate and phenylephrine. Contrasting this, an inhibitor targeting the ERK pathway, U0126, did not show a difference in HLU in its effect against phenylephrine or PDBU. This finding was supported by a decrease in phosphorylation of p38MAPK in HLU relative to control after stimulation with PDBU or phenylephrine, but no change relative to control in ERK phosphorylation. Downstream of both of these pathways, caldesmon phosphorylation was decreased in HLU relative to control after both stimulants.