Affiliations: Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA | Department of Physiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA | Department of Pathology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
Abstract: We studied the early pathophysiological response of lenticulostriate arterioles in rats in three models of human conditions associated with stroke: (a) chronic angiotensin II‐hypertension; (b) chronic nicotine administration; (c) oxidative endothelial injury. In all three models, quantitative patch clamp analysis of freshly isolated vascular smooth muscle cells from lenticulostriate arterioles and posterior cerebral arteries showed significant increases in activity of functional L‐type calcium channels that were due to an increase in open channel probability, with no change in other biophysical properties or in channel expression. In addition, all three models showed evidence of endothelial dysfunction, but of a different nature in the three. With chronic angiotensin II‐hypertension, but not in the other two models, endothelial nitric oxide synthase (eNOS) was dysfunctional, was mislocalized away from its normal abluminal location, and was accumulated in peri‐nuclear Golgi. By contrast, the other two models showed no mislocalization of eNOS, but instead showed evidence of oxidative stress in endothelium, with up‐regulation of superoxide dismutase and hexose kinase. All three models showed significant up‐regulation of expression of proliferative cell nuclear antigen (PCNA) (PCNA index, 70–80%) in arterioles in situ, which is associated with increased activation of the nuclear transcription factor, phospho‐cAMP response element binding protein (phospho‐CREB). In addition, calmodulin‐dependent protein (CaM) kinase II was activated, in concert with the activation of L‐type calcium channels. Furthermore, blockers of either L‐type calcium channels (amlodipine) or of CaM kinase II (KN‐93) completely prevented the activation of CREB and the up‐regulation of PCNA in arterioles. Our findings demonstrate that abnormal regulation of L‐type calcium channels is directly responsible for abnormal proliferative responses in vascular smooth muscle in various forms of cerebral arteriolar injury associated with endothelial dysfunction.
