CEREBAL ARTERIAL ADVENTITIA AND VASOSPASM

Project: Research project

Project Details

Description

Chronic cerebral vasospasm is a major cause of morbidity and mortality
in patients with subarachnoid hemorrhage. Pathogenesis of vasospasm is
not completely understood, but existing evidence suggests that
impairment of nitric oxide vasodilator function is an important
mechanism underlying narrowing of arteries exposed to autologous blood.
We hypothesize that increased biosynthesis of nitric oxide in adventitia
of cerebral arteries may cause vasodilatation and prevent development
of vasospasm. To test this hypothesis, we over-expressed recombinant
endothelial nitric oxide synthase (eNOS) gene in adventitial fibroblasts
of cerebral arteries by adenoviral-mediated gene transfer. This model
provides unique opportunity to characterize the effects of nitric oxide
released from adventitia on regulation of vasomotor reactivity, as well
as signal transduction pathways coupled to activation of recombinant
eNOS protein. For instance, preliminary findings indicate that in our
model, vasoconstrictor effect of a putative mediator of vasospasm,
endothelin-1, is reversed to vasodilatation. This reversal is
apparently due to endothelin-1-induced activation of recombinant eNOS
protein expressed in adventitia. We propose to study expression and
function of recombinant eNOS gene in adventitia of cerebral arteries by
immunohistochemistry,. measurements of eNOS enzymatic activity,
radioimmunoassay of cyclic GMP and in vitro and in vivo analysis of
vasomotor reactivity of tansduced arteries."Double hemorrhage" canine
model of cerebral vasospasm will be used to study effects of the
recombinant eNOS gene on vascular tone of spastic arteries. We
anticipate that experiments propose in this application will determine
whether eNOS over-expression in the adventitia can serve as a substitute
source of nitric oxide, and whether this approach can be used to restore
nitric oxide biosynthesis in cerebral arterial wall. Our studies will
also expand the knowledge base concerning the vascular biology of
adventitia, and its role as a target for transfer and expression of
therapeutically beneficial recombinant proteins.
StatusFinished
Effective start/end date1/1/9912/31/02

ASJC

  • Medicine(all)
  • Neuroscience(all)