PKC and Rho in vascular smooth muscle: activation by BOXes and SAH CSF

Cerebral vasospasm (CV) remains a significant cause of delayed neurological deficit and ischemic damage after subarachnoid hemorrhage (SAH), despite intensive research effort. The current lack of an effective therapeutic approach is somewhat due to our lack of understanding regarding the mechanism by which this pathological constriction develops. Recent evidence implicates bilirubin oxidation products (BOXes) in the etiology of CV after SAH: BOXes are found in cerebrospinal fluid from SAH patients with symptomatic or angiographically visible vasospasm (CSFV) but not in CSF from SAH patients with no vasospasm (CSFC). We have previously published research suggesting that the etiology of CV comprises two components: a physiological stimulation to constrict and a pathological failure to relax. Both these components are elicited by CSFV, but not CSFC, and BOXes synthesized in the laboratory potentiate physiological constriction in arterial smooth muscle in vitro, and elicit contraction in pial arteries in vivo. In this paper, we will present our results concerning the action of BOXes on arterial smooth muscle constriction, compared with CSFV. We will also present evidence implicating temporal changes in PKC isoforms and Rho expression in both BOXes- and CSFV-elicited smooth muscle responses.