Biology subjects

Matchkov, V. V.

Publications and source records attributed to Matchkov, V. V..

3 recordsLinked to original sources

bioRxiv2024

A KCa 2.2/2.3 opener reverses ET-1 induced NLRP3 activation in hypertensive mice

Hypertension-induced erectile dysfunction is associated with endothelial dysfunction in the corpus cavernosum. Membrane depolarization activates the NLRP3 inflammasome, with downregulation of endothelial Ca2+-activated K+ channels type 2.3 (KCa 2.3) and upregulation of endothelin-1 (ET-1) linked to erectile dysfunction. However, underlying mechanisms remain incompletely understood. We hypothesized that activating KCa 2.2/2.3 channels reverses erectile dysfunction and ET-1-induced NLRP3 activation in hypertensive DOCA/salt mice. Hypertension was induced in mice using a DOCA/salt model, with unilaterally nephrectomized mice as controls. We measured blood pressure, intracavernous pressure (ICP), and corpus cavernosum (CC) contractility, and performed immunoblots for KCa 2.3, caspase-1, and interleukin-1{beta} (IL-1{beta}). DOCA/salt mice showed impaired erectile function and increased IL-1{beta} activity and KCa 2.3 expression. Treatment with the endothelin receptor antagonist bosentan or the KCa 2.2/2.3 channel opener NS13001 reversed these dysfunctions and reduced ET-1-induced NLRP3 activation. NS13001 also restored decreased currents in endothelial cells exposed to ET-1. These findings establish that hypertension-induced erectile dysfunction involves an ET-1/membrane depolarization/NLRP3 inflammasome axis in corpus cavernosum endothelial cells, and that targeting endothelial KCa2.2/2.3 channels represents a promising therapeutic strategy to counteract erectile dysfunction. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=109 SRC="FIGDIR/small/611748v2_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@c4ed5org.highwire.dtl.DTLVardef@b915corg.highwire.dtl.DTLVardef@1744cc9org.highwire.dtl.DTLVardef@5d47d9_HPS_FORMAT_FIGEXP M_FIG Graphic abstract Overview of the KCa2.2/2.3 regulation on the ET-1-induced NLRP3 inflammasome activation in ECs. NLRP3 inflammasome activation in ECs depends on endothelin receptor B. On activation, NLRP3 recruits and forms a complex with ASC as well as procaspase 1. In the final step, the assembled inflammasome platform cleaves pro-caspase-1, and caspase-1 cleaves pro-IL-1 to activate IL-1. NS13001 activates KCa2.2/2.3, which inhibits ET-1-induced NLRP3 activation. Apamin inhibits KCa2.2/2.3 opening. Bosentan directly inhibits ETB receptors in ECs, preventing the NLRP3 inflammasome activation. C_FIG

pharmacology and toxicology↗

bioRxiv2023

SorCS2 modulates neurovascular coupling via glutamatergic and calcium signaling in astrocytes

AO_SCPLOWBSTRACTC_SCPLOWSorCS2 is involved in trafficking of membrane receptors and transporters. SorCS2 is implicated in brain disorders, but the mechanism remains uncertain. We hypothesized that SorCS2 expression is important for neurovascular coupling. Brains from P8 and 2-month-old wild type mice were stained for SorCS2 and compared to SorCS2 knockouts (Sorcs2-/-). Changes in cerebral perfusion in response to sensory stimulation, i.e., neurovascular coupling, were compared in vivo. Neurovascular coupling was also assessed ex vivo in brain slices loaded with calcium-sensitive dye. Proteomics of astrocytes was analyzed for ingenuity pathways. SorCS2 was strongly expressed in astrocytic endfeet of P8 mice but only in few astrocytes from 2-month-old brains. Sorcs2-/- mice demonstrated reduced neurovascular coupling. This was associated with reduced astrocytic calcium response to neuronal excitation in Sorcs2-/- mice. No difference in cerebral artery caliber nor in endothelial function was seen between wild type and Sorcs2-/- mice. Proteomics indicated reduced glutamatergic signaling and suppressed calcium signaling in Sorcs2-/- astrocytes. We suggest that SorCS2 expression is important for neurovascular coupling due to modulation of glutamatergic and calcium signaling in astrocytes.

neuroscience↗

bioRxiv2022

Microcirculatory dysfunction associates with neurovascular uncoupling in peri-ischemic brain regions after ischemic stroke

BackgroundDespite recanalization after ischemic stroke, neurovascular coupling, i.e., the local hyperaemic response to neuronal activity, is impaired in peri-ischemic brain regions. Reduced neurovascular coupling may contribute to neurological deterioration over time. The mechanism underlying dysfunctional neurovascular coupling following stroke is largely unknown. MethodsMice implanted with chronic cranial windows were trained for awake head-fixation prior to experiments. One hour occlusion of the anterior middle cerebral artery branch was induced using single vessel photothrombosis. Cerebral perfusion and neurovascular coupling were assessed by optical coherence tomography and laser speckle contrast imaging. Capillaries and pericytes were studied in perfusion-fixed tissue by labelling lectin and platelet-derived growth factor receptor {beta}. ResultsArterial occlusion induced on average 11 spreading depressions over one hour associated with substantially reduced blood flow in the peri-ischemic cortex. Approximately half of the capillaries in the peri-ischemic area were no longer perfused 3 and 24 hours after reperfusion, which was associated with constriction of an equivalent proportion of peri-ischemic capillary pericytes. The capillaries in the peri-ischemic cortex that remained perfused showed increased prevalence of dynamic flow stalling. Whisker stimulation led to reduced neurovascular coupling responses in the sensory cortex corresponding to the peri-ischemic region 3 and 24 hours after reperfusion. ConclusionArterial occlusion led to constriction of pericytes in the peri-ischemic cortex associated with long-lasting microcirculatory failure. This reduced capillary capacity may, at least in part, underlie impaired neurovascular coupling in peri-ischemic brain regions after stroke and reperfusion.

physiology↗