Translational Medicine III.
Éva Pál1,2, Dorina Nagy1, László Hricisák1,2, Guillaume Peter Walford1, Gábor Karácsony1, Szabolcs Várbíró3, Zoltán Benyó1,2
1 Institute of Translational Medicine, Semmelweis University, Budapest
2 Eötvös Lóránd Research Network, Semmelweis University (ELKH-SU), Cerebrovascular and Neurocognitive Disorders Research Group, Budapest
3 Department of Obstetrics and Gynecology, Semmelweis University, Budapest
Introduction: Cerebrovascular diseases belong to the leading causes of death and disability worldwide. Among several risk factors, vitamin D deficiency and altered sex hormone status (i.e. menopause or hyperandrogenism) may increase the risk and severity of cerebrovascular disorders.
Aims: We aimed to analyse the combined effects of vitamin D receptor (VDR) deficiency and androgen excess/estrogen deprivation on the cerebrovascular adaptation to unilateral carotid artery occlusion (CAO), a common cause of ischemic stroke.
Methods: Experiments were performed on adult female mice carrying a functionally inactive VDR (VDR∆/∆) and wild-type (WT) littermates. The mice were assigned to six experimental groups: intact controls (WT, VDR∆/∆), ovariectomized (OVX-WT, OVX-VDR∆/∆) and testosterone treated (TT-WT, TT-VDR∆/∆) groups. The ovaries were removed five weeks before the in vivo cerebrocortical blood flow (CoBF) measurements and similarly, testosterone treated mice received transdermal treatment for five weeks before them. The CoBF changes after CAO were analysed in three cerebrocortical regions (frontal, parietal, temporal) in both hemispheres using in vivo laser speckle imaging. Physiological parameters of mice were determined during and after the CoBF measurements.
Results: Physiological parameters (arterial blood pressure, blood gas and acid-base values) did not differ between the groups. The CoBF of the contralateral regions following CAO was not affected by the absence of VDR signaling or androgen excess/estrogen deprivation. On the contrary, in the ipsilateral hemisphere, TT-VDR∆/∆ mice had the most delayed recovery after CAO in all regions. In the frontal region, TT-VDR∆/∆ mice had a significantly higher perfusion deficit compared to WT, VDR∆/∆, and OVX-WT mice. Similarly, TT-VDR∆/∆ mice suffered from the most prolonged hypoperfusion compared to WT and VDR∆/∆ mice in the parietal region, as well as to WT and OVX-WT mice in the temporal region.
Conclusion: Surprisingly, ovariectomy did not undermine the compensatory mechanisms after CAO in VDR deficient mice. Androgen excess with VDR deficiency resulted in a prolonged hypoperfusion in all regions of the ipsilateral cortex, which implies a vasoregulatory dysfunction that may aggravate the outcome of an ischemic stroke.
Funding: ÚNKP-22-4-II-SE-17, PD-143327, K-125174, K-139230, EFOP-3.6.3-VEKOP-16-2017-00009