Biology subjects

Sandow, S. L.

Publications and source records attributed to Sandow, S. L..

3 recordsLinked to original sources

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↗

bioRxiv2019

Intercellular Conduction Optimizes Arterial Network Function and Conserves Blood Flow Homeostasis during Cerebrovascular Challenges

Cerebral arterial networks match blood flow delivery with neural activity. Neurovascular response begins with a stimulus and a focal change in vessel diameter, which by themselves is inconsequential to blood flow magnitude, until they spread and alter the contractile status of neighboring arterial segments. We sought to define the mechanisms underlying integrated vascular behavior and considered the role of intercellular electrical signalling in this phenomenon. Electron microscopic and histochemical analysis revealed the structural coupling of cerebrovascular cells and the expression of gap junctional subunits at the cell interfaces, enabling intercellular signaling among vascular cells. Indeed, robust vasomotor conduction was detected in human and mice cerebral arteries after focal vessel stimulation; a response attributed to endothelial gap junctional communication, as its genetic alteration attenuated this behavior. Conducted responses was observed to ascend from the penetrating arterioles, influencing the contractile status of cortical surface vessels, in a simulated model of cerebral arterial network. Ascending responses recognised in vivo after whisker stimulation, were significantly attenuated in mice with altered endothelial gap junctional signalling confirming that gap junctional communication drives integrated vessel responses. The diminishment in vascular communication also impaired the critical ability of the cerebral vasculature to maintain blood flow homeostasis and hence tissue viability, after stroke. Our findings establish the integral role of intercellular electrical signalling in transcribing focal stimuli into coordinated changes in cerebrovascular contractile activity and expose, a hitherto unknown mechanism for flow regulation after stroke.\n\nSignificanceNeurovascular responses are viewed as a one step process whereby stimuli derived from neural cells focally diffuse to a neighboring vessel, altering its contractile state. While focal changes in tone can subtly tune flow distribution, they cant substantively change \"perfusion magnitude\" as vascular resistance is broadly distributed along the cerebral arterial tree. We report that nature overcomes this biophysical constraint by conducting electrical signals among coupled vascular cells, along vessels, and across branch points. Our quantitative exploration of intercellular conduction illustrates how network coordination optimizes blood flow delivery in support of brain function. Diminishing the ability of vascular cells to electrically communicate, mitigates the brains ability to regulate perfusion during functional hyperemia and after stroke, the latter advancing tissue injury.

neuroscience↗

bioRxiv2018

Membrane Lipid-KIR2.x Channel Interactions Enable Hemodynamic Sensing in Cerebral Arteries

Inward rectifying (KIR) K+ channels are present in cerebral arterial smooth muscle and endothelial cells, a tandem arrangement suggestive of a dynamic yet undiscovered role for this channel. We explored whether vascular KIR channels were uniquely modulated by membrane lipids and hemodynamic stimuli. A KIR current was isolated in smooth muscle and endothelial cells of rat cerebral arteries and molecular analyses confirmed KIR2.1/KIR2.2 mRNA and protein expression. Electrophysiology next revealed that endothelial KIR was sensitive to phosphatidylinositol 4,5- bisphosphate (PIP2), with depletion impairing flow-induced activation of the channel. In contrast, smooth muscle KIR was sensitive to membrane cholesterol, with sequestration blocking pressures ability to inhibit this channel. Membrane lipids helped confer KIR mechanosensitivity to intact arteries; virtual models then reconceptualised KIR as a dynamic regulator of basal tone development. We conclude that specific membrane lipid-KIR interactions enable unique channel populations to sense hemodynamic stimuli and set brain perfusion.

neuroscience↗