Role of Pial Microvasospasms and Leukocyte Plugging for Parenchymal Perfusion after Subarachnoid Hemorrhage Assessed by In Vivo Multi-Photon Microscopy.

Julian Schwarting,Nikolaus Plesnila,Nicole Angela Terpolilli,Hanhan Liu,Kathrin Nehrkorn

doi:10.3390/ijms22168444

Abstract

Subarachnoid hemorrhage (SAH) is associated with acute and delayed cerebral ischemia. We suggested spasms of pial arterioles as a possible mechanism; however, it remained unclear whether and how pial microvasospasms (MVSs) induce cerebral ischemia. Therefore, we used in vivo deep tissue imaging by two-photon microscopy to investigate MVSs together with the intraparenchymal microcirculation in a clinically relevant murine SAH model. Male C57BL/6 mice received a cranial window. Cerebral vessels and leukocytes were labelled with fluorescent dyes and imaged by in vivo two-photon microscopy before and three hours after SAH induced by filament perforation. After SAH, a large clot formed around the perforation site at the skull base, and blood distributed along the perivascular space of the middle cerebral artery up to the cerebral cortex. Comparing the cerebral microvasculature before and after SAH, we identified three different patterns of constrictions: pearl string, global, and bottleneck. At the same time, the volume of perfused intraparenchymal vessels and blood flow velocity in individual arterioles were significantly reduced by more than 60%. Plugging of capillaries by leukocytes was observed but infrequent. The current study demonstrates that perivascular blood is associated with spasms of pial arterioles and that these spasms result in a significant reduction in cortical perfusion after SAH. Thus, the pial microvasospasm seems to be an important mechanism by which blood in the subarachnoid space triggers cerebral ischemia after SAH. Identifying the mechanisms of pial vasospasm may therefore result in novel therapeutic options for SAH patients.

Highlights

Microcirculatory dysfunction is a hallmark of early brain injury (EBI) after subarachnoid hemorrhage (SAH) [1,2,3,4,5,6]
We show that spasms of pial microvessels following SAH occur more frequently than previously thought, i.e., in almost two thirds of all vessels, and, more importantly, that these spasms cause a 60% reduction in parenchymal perfusion
Plugging of capillaries by leukocytes occurs after SAH but does not seem to add much to the already existing perfusion deficit

Summary

Introduction

Introduction iationsMicrocirculatory dysfunction is a hallmark of early brain injury (EBI) after subarachnoid hemorrhage (SAH) [1,2,3,4,5,6]. Constrictions of pial arterioles, or microvasospasms (MVSs), have been detected in SAH patients [7,8] as well as in animal models of SAH [9,10,11] and are thought to significantly contribute to post-hemorrhagic ischemia. It is unclear whether spasms of pial arterioles result in a reduction in parenchymal perfusion. Adhesion of inflammatory leukocytes occurs early after SAH in superficial brain vessels [11] and may cause accumulation of neutrophils in brain parenchyma within minutes of SAH [17,18,19].

Methods

Discussion

Conclusion