Abstract

Subarachnoid hemorrhage is a subtype of stroke that is caused by a bleeding into the subarachnoid space. Cerebral ischemia develops early after the bleeding and has a negative influence on outcome in patients. The underlying pathophysiology triggering early ischemia has not been characterized in detail. Suggested pathomechnisms are pial microvasospasm, endothelial dysfunction and microthrombosis. The aim of the current thesis was to characterize and reveal the pathophysiology of microcirculatory perfusion deficits early after subarachnoid hemorrhage. The main hypothesis was that pericytes constrict upon subarachnoid hemorrhage and thereby induce capillary spasm and hamper parenchymal blood flow dynamics. We found that pial arterioles constrict in three different characteristic patterns and that spastic vessel segments were continuously covered with vascular smooth muscle cells. Superficial microvasospasm was associated with reduced blood flow velocity and significant reduction of endothelial intracellular Ca2+ concentration which may be a trigger for endothelial dysfunction. Reduced blood flow velocity in combination with reduced vessel diameter diminished total blood volume that reached the parenchymal microcirculation via penetrating arterioles. This led to a severe reduction of perfused capillary volume in the cortex. Leukocyte numbers that were sticking in capillaries and venules were increased after subarachnoid hemorrhage but their numbers were too low to explain severe perfusion deficits. Capillaries revealed a significantly reduced vessel diameter after subarachnoid hemorrhage, however vessel narrowings were not co-localizing with sites where pericytes were associated to capillaries. Furthermore pericytes neither underwent cell death nor migrated away from capillaries within 24 hours after the bleeding. In conclusion we showed that microvasospasm on the brain surface lead to severe perfusion deficits in the parenchyma. Microvasospasm are probably induced by vascular smooth muscle cells and are accompanied by reduced intracellular Ca2+ concentration in endothelial cells. Pericytes do not play a major role in the pathophysiology of early ischemia after subarachnoid hemorrhage: they neither migrate, nor die or induce capillary spasm.