Stroke, Sex and Vascular Receptor Changes in the Brain

Sammanfattning: Stroke is a severe cerebrovascular disease in which the neuronal tissue and vasculature of the brain undergo ischemia-evoked alterations. We have demonstrated an increased expression of cerebrovascular contractile receptors in the brain. This is hypothesized to mitigate cerebral blood flow and exacerbate tissue damage after stroke. An increased contractile property of these receptors has been demonstrated to occur by MEK/ERK1/2 signaling. The majority of pre-clinical studies on stroke are performed in young healthy male animals, despite the fact there is a difference in male and female stroke incidence. The present thesis therefore aimed to investigate the status of vascular receptor changes after experimental stroke and organ culture, with two focus areas that previously have been missing – studies on human material and female subjects. In human cerebral arteries, we found that increased vasoconstriction of 5-HT1B, AT1 and ETB receptors during organ culture, a model of ischemic-like receptor changes, is mediated by B-Raf/MEK/ERK1/2 signaling. Although, increased mRNA and protein of these receptors were found in arteries from both sexes, the contraction to Ang II and ET-1 was markedly lower in female arteries. Focal cerebral ischemia in female rats induced an enhanced contractile property of cerebrovascular ETB receptors, similar to previous observations in males. Ovariectomy, and thereby loss of progesterone and estrogen, resulted in less ischemia-induced ETB receptor upregulation. Hormone therapy with progesterone, but not estrogen, reversed these changes. The increased ETB receptor expression and vasoconstriction after cerebral ischemia in female rat was demonstrated to be mediated by MEK/ERK1/2 signaling. MEK1/2 inhibition attenuated the ETB receptor upregulation and improved the neurological outcome. The present thesis demonstrates for the first time sex differences in vascular function of human cerebral arteries. The underlying mechanism in decreased responsiveness of female arteries remains to be elucidated. This may involve differences in receptor coupling or signal transduction influenced by female sex steroid hormones, or biological sex. Our experimental studies on stroke suggest the loss of progesterone after ovariectomy suppresses ischemia-induced ETB receptor upregulation. Further, the signal transduction pathway involved in vascular receptor changes after cerebral ischemia is suggested to be similar in both sexes. MEK1/2 inhibition is therefore a promising therapeutic target for stroke therapy in both males and females.