Capillary flow disturbances after experimental subarachnoid hemorrhage: A contributor to delayed cerebral ischemia?

Abstract

Background:The high mortality and morbidity after SAH is partly due to DCI, which is traditionally ascribed to development of angiographic vasospasms. This relation has been challenged, and capillary flow disturbances are proposed as another mechanism contributing to brain damage after SAH.Objective: To investigate capillary flow changes 4 days following experimental SAH.Methods: SAH was induced by endovascular perforation of circle of Willis. We used TPM to evaluate blood flow characteristics. Cortical capillary diameters were investigated by both TPM and histology. Results:We found elevated CTH and MTT of blood in SAH mice compared to sham animals. We observed capillaries with stagnant RBCs, and capillaries with increased RBC LD in the SAH group, suggesting severe blood maldistribution among cortical capillaries. Favoring that these capillary flow changes were primary to upstream vasoconstrictions, TPM showed no significant differences in arteriolar diameter between groups, while histological examination showed reduced capillary diameter in SAH group. Conclusion:Our study shows profound subacute hypoperfusion and capillary flow disturbances in a mouse SAH model and suggests that these changes are the result of changes in capillary function, rather than upstream vasospasm. K E Y W O R D S capillary transit time heterogeneity, delayed cerebral ischemia, microcirculation, subarachnoid hemorrhage, two-photon microscopy 1 | INTRODUC TI ON SAH typically results from the rupture of intracranial aneurysms and constitutes a subset of hemorrhagic strokes. Despite recent advances in acute management of aneurysmal hemorrhages, SAH remains associated with high mortality and poor functional outcome. 1,2 SAH comprises 3%-5% of all strokes, but imposes disproportionate socioeconomic costs by affecting young individuals, who are active in the workforce. 3 Accordingly, half of the SAH patients are under the age of 55 at the time of their SAH insult. 4-7 While one in five die before receiving any medical attention or die during transportation, half of the SAH patients die within 4 weeks after the first attack. 8,9

Sural Nerve Perfusion in Mice

“…The diameter of vessels within which we recorded RBC dynamics using TPLSM is similar to that described in brain tissue of mice and rats (Kleinfeld et al, 1998;Stefanovic et al, 2008;Gutierrez-Jimenez et al, 2016;Dorr et al, 2017;Anzabi et al, 2019) and in rat tibial nerves (Sakita et al, 2014(Sakita et al, , 2016. This is in contrast to a detailed morphological study of the more proximal, sciatic nerve vasculature in rats and mice, where the smallest nerve vessel sizes were between 8 and 9 µm in diameter, larger than muscle tissue microvessels (ca.…”

“…These differences might be due to the different methods used to measure vessel diameters. In vivo microscopy, used in our study and in the five studies of the brain (Kleinfeld et al, 1998;Stefanovic et al, 2008;Gutierrez-Jimenez et al, 2016;Dorr et al, 2017;Anzabi et al, 2019), reveals vessel diameters without artifacts induced by tissue fixation, but also selects vessels with single file RBC passage, possibly underestimating mean tissue microvessel diameter. In the study of the rat tibial nerve, whole vasculature was perfused with gelatinized contrast and sections were studied (Sakita et al, 2014(Sakita et al, , 2016.…”

“…The vasodilatory effect might have also lead to an overestimation of vessel diameters. However, even in that case, capillary RBCv in mouse sural nerves is higher than in the brain, while diameters of vessels with single file RBC passages are comparable to those in the brain (Dorr et al, 2017;Anzabi et al, 2019). Although hemodynamic measurements in the brain tissue of awake mice are becoming more common (Roche et al, 2019), preparation and fixation of the hindlimb in awake mice is currently not done.…”

Small Vessels Are a Big Problem in Neurodegeneration and Neuroprotection

“…Like in cerebral ischemia, there is profound increase in capillary transit time heterogeneity after subarachnoid hemorrhage, caused by microarteriolar constrictions (165), reactive oxygen radicals, astrocyte end-feet swelling, leukocyte increase, and activation (39). There are numerous capillaries either without RBCs but with plasma, or with stationary RBCs in them (166). Capillaries with smaller diameters have been shown to have less probability to be perfused with RBCs (167).…”

Longitudinal, Multiparametric MRI Assessment of repetitive mild TBI in rats

“…Repetitive mTBI induces very mild and diffuse a change in damage, which typically cannot be detected by conventional brain scanning methods. However, microscopy has revealed axonal injury [1,10], dendritic beading and retraction [11,12], reduction in arteriolar and capillary diameter, and astroglial swelling after mTBI [13][14][15]. While such immunohistological information is vital to understand the underlying mechanisms of injury, it can only be obtained from animal models and/or cadaver brains.…”