Keywords

1 Introduction

We recently showed the transition from brain capillary (CAP) to MVS flow with increased intracranial pressure (ICP), it’s role in the loss of cerebral blood flow (CBF) autoregulation and the circulatory isolation of injured brain tissue by perfusion through microvascular shunts (MVS) [5]. Our investigations into MVS were initiated by the study by Miller et al. in 1972 [1] reporting an unexplained decrease in the critical cerebral perfusion pressure (CPP) threshold of CBF autoregulation from 50 to 30 mmHg when CPP was decreased by increasing ICP instead of decreasing arterial pressure as conventionally done in studies [2, 3]. We hypothesized that the decrease in critical CPP when ICP rather than mean arterial pressure (MAP) was used to decrease CPP, was due to MVS flow resulting in a falsely elevated CBF and apparently maintained CBF at a lower critical CPP of 30 mmHg. We then showed brain MVS in our studies using two photon laser scanning microscopy (2PLSM) [4, 5].

2 Evidence on Microvascular Shunts

Shunt Flow in Traumatic Brain Injury

A dramatic example of non-nutritive shunt flow after traumatic brain injury was observed in a 7-year-old female who suffered severe left hemispheric infarction and at 7 days after injury was placed under barbiturate coma for treatment of intracranial hypertension (Fig. 1). CBF measured by stable xenon-CT showed that the infarcted left hemisphere was extremely hyperemic whereas the right hemisphere was hypoperfused due to barbiturate suppression of metabolism and depressed CBF. This remarkable demonstration of MVS triggered our search to prove the occurrence of brain MVS.

Fig. 1
Three C T scan images of an injured brain on top and stable xenon C B F maps at the bottom. It illustrates the infracted left hemisphere.

CT scan (top) and stable xenon CBF maps (bottom) a 7 year old female 7 days after severe brain trauma under barbiturate coma for high ICP. The left hemisphere is completely infarcted and the right hemisphere normal. CBF in the normal hemisphere is depressed by barbiturate indicating flow-metabolism coupling. The left hemisphere shows marked hyperemia and “nonnutritive flow” loss off CBF autoregulation

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MVS in Human Cerebrum

Histological sections of human cerebrum suggest bridges of vessels without intervening capillary beds in the microvasculature [6]. These MVS 10–25 μm diameter are larger than capillaries which were measured at about 3–8 μm in outer diameter and arterio-venous and veno-venous anastomoses in the range of 25 μm.

Cerebral Capillary Flow Autoregulation

Hudetz et al. [7] reported two populations of microvessel flow velocities; one above and one below one mm/sec. High flow velocity microvessels showed no autoregulation whereas low flow velocity vessels showed constant flow velocity until the lower limit of autoregulation was reached.

Microvascular Shunts with Increased ICP

Our first definitive evidence of MVS in the healthy rat brain was by increasing ICP with a reservoir of mock CSF with a catheter into the cisterna magna using two photon laser scanning microscopy (2PLSM) [4, 5]. Increased ICP showed increased flow velocity in vessel diameters >10 μm which was not observed when CPP was decreased by decreasing mean arterial pressure (MAP) (Fig. 2).

Fig. 2
Three scatterplot graphs of the control group, I C P group and M A P group on velocity versus diameter plane. 1. The dots clustered between (0,4) and (2,15) on the y and x axes respectively. 2. The dots clustered highly between (0,2) and (1,7) and beyond that scatter throughout. 3. Most of the dots clustered between (0,1) and (1,10). All the values are approximated.

(a) normal CPP (70 mmHg) and by (b) decreased CPP to 30 mmHg by increasing ICP. (c) Decreased MAP to reduce the CPP to 30 mmHg [5]. (Reproduced with the permission of the Editor of J Neurotrauma [4])

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Consistent with the effect of MVS as non-nutritive and without clearance of metabolic waste products or gas exchange, tissue hypoxia develops as indicated by the increase in NADH, i.e. a reflection of tissue hypoxia or low oxygen, with increasing ICP which was partially mitigated by increasing CPP. The effect of increasing ICP which also increased brain edema (water content) was partly mitigated by increasing CPP. Increasing ICP caused a progressive decrease in CAP/MVS ratio and shunting with increasing hypoxia and Doppler flux.

3 Low Blood Flow and Shear Rate on Endothelial Function

There are multiple shear stress related controls for blood vessels in the circulation in large arteries, small arteries to arterioles, capillaries, venules and veins [8]. For each of these vessels of different calibers, there are processes related to: blood vessel growth, angiogenesis, re thrombolysis and inflammatory processes such as sepsis all controlled by shear stresses in the blood vessels [9, 11].

The shear rate on the endothelium of capillaries is highest as it is inversely proportional to the third power of the vessel diameter [8, 11]. Endothelial shear rate plays an important role in endothelial function through the glycocalyx, a carbohydrate-rich layer 0.2–0.5 μm thick gel-like layer lining the luminal membrane of the endothelium (8, 10, 12). It connects to the endothelium by core molecules containing proteoglycans and glycoproteins [12] triggered by the shear rate and torque applied to endothelial cells (Fig. 3). It consists of proteoglycans 50–90% of which is heparin sulfate and glycoproteins anchored to the endothelium by glycosaminoglycans. It maintains the colloid osmotic gradient of the vascular barrier; regulates vascular exchange of water and solutes and leucocyte adhesion; provides binding sites for several molecules antithrombin III, lipoprotein lipase vascular endothelial growth factor; and acts as a shear stress sensor and regulator [12]. The glycocalyx controls capillary endothelial function as the interface between the tissue and the circulation.

Fig. 3
An illustration of endothelial glycocalyx is depicted schematically, with its major components. Soluble proteoglycan, hyaluronic acid, glycoprotein and a few other components are mentioned.

Schematic representation of the endothelial glycocalyx, showing its main components. Left: The endothelial glycocalyx observed in vivo as a red blood cell exclusion zone, located on the luminal side of the vascular endothelium. It consists of membrane bound and soluble molecules. Right: Components of the endothelial glycocalyx [10]. (Reproduced Springer Verlag)

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4 Low Blood Flow and MVS in the Final Common Pathway in Cerebrovascular Disease

The role of low blood flow in cerebrovascular disease is increasingly recognized in the pathogenesis of all cerebrovascular diseases including vascular dementia, Alzheimer’s Disease [13]. MVS occur primarily in the deep cortical white matter and in the periventricular white matter where white matter hyperintensities (WMH) are most frequently observed. The role of MVS in the pathophysiology of cerebrovascular disease may be a means of isolating injured tissue from further perfusion shunting blood around dead and edematous tissue inducing further edema in injured tissue. MVS do not conduct nutrient nor gas exchange with tissue which would reduce further brain edema development in injured tissue.