Cerebral microcirculatory failure after subarachnoid hemorrhage is reversed by hyaluronidase

Abstract

Aneurysmal subarachnoid hemorrhage remains one of the more devastating forms of stroke due in large part to delayed cerebral ischemia that appears days to weeks following the initial hemorrhage. Therapies exclusively targeting large caliber arterial vasospasm have fallen short, and thus we asked whether capillary dysfunction contributes to delayed cerebral ischemia after subarachnoid hemorrhage. Using a mouse model of subarachnoid hemorrhage and two-photon microscopy we showed capillary dysfunction unrelated to upstream arterial constriction. Subarachnoid hemorrhage decreased RBC velocity by 30%, decreased capillary pulsatility by 50%, and increased length of non-perfusing capillaries by 15%. This was accompanied by severe brain hypoxia and neuronal loss. Hyaluronidase, an enzyme that alters capillary blood flow by removing the luminal glycocalyx, returned RBC velocity and pulsatility to normal. Hyaluronidase also reversed brain hypoxia and prevented neuron loss typically seen after subarachnoid hemorrhage. Thus, subarachnoid hemorrhage causes specific changes in capillary RBC flow independent of arterial spasm, and hyaluronidase treatment that normalizes capillary blood flow can prevent brain hypoxia and injury after subarachnoid hemorrhage. Prevention or treatment of capillary dysfunction after subarachnoid hemorrhage may reduce the incidence or severity of subarachnoid hemorrhage-induced delayed cerebral ischemia.

Requisite ischemia for spreading depolarization occurrence after subarachnoid hemorrhage in rodents

“…After SAH, focal ischemia can develop via a number of mechanisms such as microvascular plugging due to in situ thrombosis or microembolization. 30 Regardless of the mechanisms precipitating ischemia, SAH-induced vascular dysfunction [31][32][33][34] diminishes collateral flow and expands the volume of ischemic tissue. We posit that focal ischemia in turn triggers peri-infarct SDs, facilitated by SAH in a delayed fashion possibly via blood breakdown products or vascular dysfunction.…”

Hippocampal Atrophy Following Subarachnoid Hemorrhage Correlates with Disruption of Astrocyte Morphology and Capillary Coverage by AQP4

“…Of note, the thickness of cortical astrocyte endfeet was examined by McConnell et al (2016) 48 h following SAH in mice. They concluded that capillary flow disturbance is not the consequence of astrocyte endfeet swelling, nor constriction of pericytes ( McConnell et al, 2016 ).…”

“…Of note, the thickness of cortical astrocyte endfeet was examined by McConnell et al (2016) 48 h following SAH in mice. They concluded that capillary flow disturbance is not the consequence of astrocyte endfeet swelling, nor constriction of pericytes ( McConnell et al, 2016 ). Our findings indicate that, at least in the hippocampus, loss of capillary coverage by AQP4 positive astrocytes and retraction of astrocyte endfeet, may affect capillary flows by disrupting neuro-capillary coupling mechanisms (see below) and BBB disruption.…”

Space Balls Revisited: Stereological Estimates of Length With Virtual Isotropic Surface Probes

“…Examples using space ball probes include; the length of dopaminergic axons, which can be related to the dopaminergic innervation and function of the striatum (Li et al, 2016 ); the length of serotoninergic (Liu et al, 2011 ) and cholinergic axons in cerebral cortex which can be related to cortical function (Nikolajsen et al, 2011 ) and the length of astrocyte processes, which can be related to immune-reactivity (McNeal et al, 2016 ). These parameters can be used to evaluate brain hemodynamics (Kubíková et al, 2018 ), tissue oxygenation (Nikolajsen et al, 2015 ), and tissue repair (Lee et al, 2005 ; McConnell et al, 2016 ) and ultimately used to develop therapeutic approaches to brain disorders. Structural parameters of potential interest and for which quantitative studies of length have yet to be carried out include microtubules, involved in intracellular transport, and neuropil threads, an expression of Alzheimer's disease.…”