Pál, Éva

Carotid artery stenosis (CAS) affects approximately 5–7.5% of older adults and is recognized as a significant risk factor for vascular cognitive impairment (VCI). The impact of CAS on cerebral blood flow (CBF) within the ipsilateral hemisphere relies on the adaptive capabilities of the cerebral microcirculation. In this study, we aimed to test the hypothesis that the impaired availability of nitric oxide (NO) compromises CBF homeostasis after unilateral carotid artery occlusion (CAO). To investigate this, three mouse models exhibiting compromised production of NO were tested: NOS1 knockout, NOS1/3 double knockout, and mice treated with the NO synthesis inhibitor L-NAME. Regional CBF changes following CAO were evaluated using laser-speckle contrast imaging (LSCI). Our findings demonstrated that NOS1 knockout, NOS1/3 double knockout, and L-NAME-treated mice exhibited impaired CBF adaptation to CAO. Furthermore, genetic deficiency of one or two NO synthase isoforms increased the tortuosity of pial collaterals connecting the frontoparietal and temporal regions. In conclusion, our study highlights the significant contribution of NO production to the functional adaptation of cerebrocortical microcirculation to unilateral CAO. We propose that impaired bioavailability of NO contributes to the impaired CBF homeostasis by altering inter- and intrahemispheric blood flow redistribution after unilateral disruption of carotid artery flow.

The understanding of cerebral autoregulation has become of notable importance due to the increased incidence of carotid artery stenosis in the elderly population which entails an increased risk of stroke, the 2nd most common cause of mortality worldwide. Many debates, regarding its exact mechanisms, exist in the scientific literature including the role of endothelial and neuronal nitric oxide (NO) synthases (eNOS and nNOS) and prostanoid mediators (PMs). According to our previous observations, eNOS, surprisingly, does not seem to play an important role in the autoregulation of the cerebrocortical blood flow (CoBF) to unilateral common carotid artery occlusion (CAO) . In our recent study we aimed to analyze the combined lack of eNOS and nNOS and the role of PMs in cerebrovascular autoregulation by analyzing the changes of CoBF after reducing the cerebral perfusion pressure by unilateral (left) CAO in wild‐type (WT), as well as in eNOS/nNOS double knock‐out (KO) male mice. The role of PMs was tested by indomethacin administration (1 mg/kg, i.p.) and in thromboxane knock‐out (TPR‐KO) male mice. Using the high temporal and spatial resolution of laser‐speckle imaging regional CoBF changes were analyzed after CAO in anesthetized adult male mice. In wild‐type animals CoBF reduction in the left temporal cortex started immediately after CAO, reaching its maximum (−27%) at 6–9 s. Thereafter, CoBF recovered close to the pre‐occlusion level within 30 s indicating the activation of regulatory pathway(s). Interestingly, the frontoparietal cerebrocortical regions also showed CoBF reduction in the left (−17–19%) hemisphere, indicating a stealing effect through pial collateral vessels from the frontoparietal to the more ischemic temporal cortex. Surprisingly, in eNOS/nNOS double KO animals the acute CoBF reduction after CAO was unaltered in all cerebrocortical regions, but the recovery of CoBF was worsened as compared to controls. Indomethacin treatment resulted in a faster recovery in the temporal region, specifically 9–21 s after the occlusion. In TPR‐KO animals, however, the recovery of the CoBF was slightly diminished. These results indicate that (1) the Willis circle alone is not sufficient to provide an immediate compensation for the loss of one carotid artery, (2) the combined lack of eNOS and nNOS impairs only the subacute phase of the recovery after unilateral CAO and (3) indomethacin treatment results in a faster recovery, probably by inhibiting the release of a vasoconstrictor prostanoid, which is not thromboxane A 2 . Support or Funding Information EFOP‐3.6.3‐VEKOP‐16‐2017‐00009, OTKA K‐125174, OTKA K‐112964, NVKP‐16‐1‐2016‐0042