Abstract
We investigated the role of protein kinase C (PKC) isoforms and tyrosine kinase in the pathophysiology of vasospasm after subarachnoid hemorrhage (SAH). In the development of vasospasm, PKCδ plays a role, and PKDα in its maintenance. These evidence were confirmed by in-situ treatment study using "two-hemorrhage" canine model. Two weeks after the first hemorrhage, the activity of PKC was declined. On the other hand, the activity of tyrosine kinase was enhanced. In the mechanism of vasospasm, the main role to sustain the vasospasm would change from PKC to tyrosine kinase. We also investigated the roles of biomechanical and phenotypic changes of cerebral arteries in the mechanism of prolonged vasospasm after SAH. Using basilar arteries in "two-hemorrhage" canine model, we chronologically measured the maximal contraction capacity and arterial stiffness until day 28. We examined histological changes of vasospastic canine basilar arteries with hematoxylin-eosin staining, and also immunohistochemically investigated the expression of smooth muscle myosin heavy chain isoforms (SMemb, SM1, and SM2), markers of phenotypic changes. Chronological changes of collagen concentration in canine basilar arteries were also measured. Angiographic cerebral vasospasm continued until day 14, then gradually relived and returned control level on day 28. The maximal contraction capacity chronologically decreased until day 21, then it showed some relief on day 28. On the other hand, stiffness of arterial wall progressed until day 28. Histological findings showed medial thickening and increase connective tissue until day 21, then returned close to the control on day 28. Because of no change of collagen concentration, increased connective tissues did not consist of collagen, but some other proteins. Immunohistochemical study using anti-SMemb, SM1, and SM2 showed enhanced expression of SMemb from day 7 to day 21 and dispappearance of SM1 and SM2. These changes returned to the normal control artery on day 28. These results indicate that biomechanical changes of vascular smooth muscle cells and phenotypic changes occurred in vasospastic canine basilar arteries. These changes might play a pivotal role to sustain prolonged cerebral vasospasm longer than 2 weeks following SAH instead of active myogenic arterial tone.
