Freeman Laboratory - Department of Surgery
Cerebrovascular Endothelium in Traumatic Brain Injury
Endothelial Ca2+ levels regulate relaxation of the blood vessels and therefore blood flow in the brain. The vascular endothelium is also critical for “blood-brain barrier” function.
Abnormal endothelial function after brain injury could contribute to
• Spasm of blood vessels
• Impaired “coupling” of blood vessels and nerves (neurovascular coupling)
• Tissue swelling (edema)
The goal of this project is to understand the changes in cerebrovascular endothelial Ca+2 signals, vasodilation, and blood brain barrier permeability after acute brain injury.
Our rational for focusing on TRPV4 channel is that activation of this Ca2+ channel has been linked to altered barrier function in other tissues. The results expected from this pilot project will support a novel mechanism that could explain the neuropathology, including edema, vasospasm, and altered neurovascular coupling, that follows acute brain injury.
Aim #1: To compare endothelial cell Ca2+ signals and vasodilation in rat cerebral arteries after TBI. We hypothesize that EC Ca2+ signaling will increase, and furthermore, increases in EC Ca2+ signaling after TBI are due to IP3 and/or TRPV4 Ca2+ channels. In addition, we expect that pressurized cerebral arteries after TBI will exhibit tonic vasodilatory influence from the endothelium. ECs will be imaged for Ca2+ signals in the presence of specific Ca2+ channel blockers to determine whether changes in Ca2+ are due to IP3 or TRPV4 Ca2+ channels. We will measure vessel diameter in pressurized intact arteries and in those that have been denuded of endothelium.
Aim #2: To determine the relationship between endothelial cell Ca2+ signals and blood brain barrier permeability after TBI. We hypothesize that after TBI, the blood brain barrier permeability will be increased, electrical resistance will be decreased, and IP3 and/or TRPV4 Ca2+ channel blockers will normalize blood brain barrier electrical resistance. BBB permeability will be studied by measuring extravasation of fluorescent dextran (4 kDa) in tissue after in situ perfusion, and by measurement of the electrical resistance across the wall of intact pial vessels, in the presence of IP3 or TRPV4 Ca2+ channel blockers.
Last modified March 13 2012 10:08 AM