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Review paper
Increased vesicular and vacuolar transendothelial transport in traumatic human brain oedema. A review

Orlando J. Castejón

Folia Neuropathol 2013; 51 (2): 93-102
Online publish date: 2013/06/26
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Introduction

Increased endothelial cell vesiculation has been earlier reported in anoxic-ischaemic lesions [30,31,36], experimental cerebral infarction [3], ionizing radiation [20], brain-stem lesion of thiamine-deficient rats [44], following intraventricular perfusion with serotonin, norepinephrine and cyclic AMP [63], ultraviolet irradiation [49], experimental seizures [46], hypertension [28,47,59], brain trauma [1,6,12-16,18,21,31,47,48], congenital hydro­cephalus [10,17], and brain tumours [23,50,53-55].

The hypothesis of “vesicular transport” stands as a ge­nerally accepted process, explaining in particular macromolecular transport in capillaries [2]. The most convincing evidence to date for a vesicular transport of protein across reactive cerebral capillaries was earlier provided by

Beggs and Waggener [1], who found that upon reproducible contusion of the spinal cord in cats, horse­radish peroxidase escaped from the vessels by means of pleo­morphic vesicles, tubules and large vacuoles.

The orientation of pinocytotic vesicles correlating with the stage of the oedematous process was first made by Wagner et al. [61], and reproduced by Cervós-Navarro et al. [19]. Sazaki et al. [49] reported a typical orientation of the micropinocytotic vesicles depending upon

the stage of the oedematous process: in the early stages, they are found preferably at the luminal side of endo­thelial cells, and later on they predominate at the abluminal endothelial cell membrane. Ferszt et al. [29] reported diffuse macro- and micropinocytotic activity in focal brain oedema due to ultraviolet irradiation as tissue water content reaches maximum values.

Casley-Smith and Carter [4] found that large vacuoles in inflamed endothelium do indeed transport macromolecules across the cells. In addition, large endo­thelial vacuoles and transendothelial vacuolar transport have been described in a large variety of pathological entities, such as brain tumours [50,53-55], anoxic-ischaemic lesions [6,8-10,13,17,21,27,30,33,34, 40,41,45], injections of Gram-negative endotoxin [24], lead encephalopathy [39], experimental allergic ence­phalomyelitis [35], and human brain oedema [6,8]. These studies show that the formation of endothelial vacuoles could be interpreted as opening of the endothelial ‘pore system’ induced by different pathological conditions [6]. Lossinsky et al. [42,43] studied the vesicular and canalicular transport structures

in endothelial cells after crude leptomeningeal damage in mice, and in cold lesion injury in cats. Castejón

[6-9] described an increased vesicular and vacuolar transendothelial transport, and formation of trans­endothelial channels in endothelial cells and pericytes in human traumatic and complicated brain injuries.

Shibata et al. [50] reported increased endothelial pinocytotic vesicle formation in human brain tumours. Claudio et al. [25] found an increased endothelial cell vesicular transport in rat experimental autoimmune encepha­lomyelitis. According to these authors, immunogold staining of endogenous albumin demonstrated the presence of albumin in cytoplasmic vesicles and in channel-like tubular structures adjacent to endothelial cell junctions. These results indicated that there

is a role for vesicles in transendothelial cell transport and oedema formation in animals with experimental autoimmune encephalomyelitis. Takano et al. [53] ob­served an increased vesicular transport in human glio­ma capillaries. Kato et al. [38] demonstrated increased numbers of vesicles and vacuoles in endothelial brain capillaries in cerebral oedema from fulminant hepa­tic failure.

Zumkeller and Dietz [65] described an increased protein vesicular transport in rats after treatment with nimodipine. Cicciarello et al. [26] found enhanced vesicular transport of horseradish peroxidase in an experimental model of whole brain after irradiation. Plateel et al. [45] examined the increased permeability of albumin after hypoxia, attributed to non-specific vesicular transport in a cell culture model of brain barrier.

Hofman et al. [37] showed an increased vascular permeability for plasma proteins in vivo induced by vascular endothelial growth factor-A (VEGF) in blood-re­tinal barrier endothelium predominantly caused by a mechanism involving active trans-endothelial transport via pinocytotic vesicles, and not by formation of en­dothelial fenestrations or vesiculo-vacuolar organelles.

Castejón et al. [15] reported an increased vesicular and vacuolar transendothelial transport in two patients with post-traumatic seizures. Lossinsky et al. [42] examined the vesicular and canalicular transport structures in the injured mammalian blood-brain barrier. Lossinsky and Shivers [43] reviewed in detail the structural pathways for macromolecular and endothelial cell transport during inflammatory conditions and brain injuries. Cipolla et al. [27] found increased apical and basolateral pinocytosis in cerebral endothelium during ischaemia/reperfusion, and elevated intravascular pressure. Castejón [10,17] described an increased vesicular and vacuolar transport in cortical capillaries from parietal and frontal cortex of patients with congenital hydrocephalus and Arnold-Chiari malformation.

Vesicular and vacuolar transport is a highly dyna­mic process currently studied in experimental animal works with electron dense tracers. The study of endothelial vesicular and vacuolar transport in human cortical biopsies is obviously limited for many reasons, such as:

a) ethical principles that limit the use of electron den­se probes in vivo, b) samples randomly obtained, c) ultrathin sections giving isolated images of endothelial cell substructures, d) great variability of the nature of traumatic agents and impact energy, and the patient’s age and state of health.

In the present review we describe the morphological evidence of increased vesicular and vacuolar transports induced by human traumatic brain injuries. Emphasis will be placed on the role played by vesicular and vacuolar transports in oedema formation and oedema resolution. The variety of endothelial cell mechanisms observed in severe vasogenic brain oedema also are analysed.

Vesicular and vacuolar transendothelial transport as morphological signs of increased cerebrovascular permeability

Resting cortical capillaries



In traumatic moderate brain oedema, some gray matter cortical capillaries exhibit a normal appearance with an inactive, resting endothelial cytoplasmic peripheral zone, characterized by straight, almost smooth, luminal plasma membrane, without pseu­dopodic expansions and scarce micro- and macropinocytotic activity. In these normal capillaries, the basement membrane appears as a compact structure formed by filaments embedded

in a homogeneous matrix. Only some free and membrane-bound clathrin-coated vesicles are encountered. The endothelial junctions are structurally intact, and

the astrocytary glial end-feet appear intimately applied to the basement membrane [6,8,11]. These “non-leaky” capillaries are not activated by the mechanical injury exerted by the intensity of brain trauma.



Activated cortical capillaries



Other capillaries are activated by the traumatic injury and show an endothelial cell luminal surface activity, exhibiting abundant luminal microvilli, presence of coated vesicles, remarkable orientation of numerous abluminal uncoated pinocytotic vesicles toward the capillary basement membrane (Fig. 1), and a lesser amount of caveolae intracellularis or ‘pits’ connected to the luminal endothelial surface, suggest­ing abluminally orientated vesicular transport [6,8].

The non-leaky segments of capillaries contain “immobile” endothelial vesicles [58], which are activated in the leaky segments by the impact energy.

Chained pinocytotic vesicles fused with each other and with tubular invaginations to form shuttle vesicles or incomplete transient transendothelial channels [7,42,43]. In addition, large spheroid or elongated vacuoles, containing hematogenous oedema fluid ap­pear free in the endothelial cytoplasm (Figs. 2 and 3). These vacuoles discharge their content directly into the basement membrane or by means of plasmalemmal vesicles. The basement membrane appears swollen, and abundant proteinaceous oedema fluid is seen separating the basement membrane from the perivascular glycogen-rich and glycogen depleted astroglial end-feet [11,14]. The latter are remarkably swollen and their limiting membranes appear fragmented.

Some actin-like filaments are attached to the va­cuole limiting membrane, suggesting that the cytoske­leton is involved in the transendothelial movement

of these vacuoles [8]. In normal capillaries the small vesicular and vacuolar transport is a random process powered by Brownian motion [4], but in the case of an enhanced cerebrovascular permeability, the participation of cytoskeletal structures is required to speed up the vacuolar and vesicular transport. A detailed study of the longitudinal sections of the capillary wall show that, in addition to the endothelial peripheral zone, the nuclear and organelle endothelial zones (Fig. 4) also exhibit surface activity, with shallow and deep invaginations of luminal plasma membrane to form protein-transporting vacuoles [6,8]. Deep invaginations of en­dothelia cell luminal membranes were also reported by Lossinski et al. [42] in experimental models of brain injury. The endothelial cell nuclear zone in normal capillaries shows a little or no micropinocytotic activity [6,51,52].

Vacuoles and vesicles actually participating in the transendothelial transport toward the basement me­mbrane could be distinguished from those internaliz­ing to some cell organelles, such as multivesicular

bodies, Golgi apparatus and lysosomes (Figs. 5 and 6). The Golgi complex appears hypertrophic with dilat­ed endoplasmic sacs and Golgi vacuoles. Deep inva­ginations of the luminal surface are formed in the vicinity of the Golgi formation phase, and numerous clathrin-coated and uncoated vesicles are observed in this area [8].

Golgi vesicles are the structural vectors of the recycled membranes [51,52]. Presumably a considerable amount of Golgi complex-derived membrane is inserted into the endothelial luminal plasmalemma to provide new membranes for the increased vesicular and vacuolar transport. This sustained over-function might induce Golgi complex hypertrophy [8,16].

Some pinocytotic vesicles are found surrounding dense cored vesicles and small lysosomes, suggesting that some amount of plasma protein is transported by plasmalemmal vesicles towards the lysosomes to be degraded by lysosomal enzymes, as an endothelial cell mechanism of oedema resolution [8,58]. At the Golgi region, uncoated and coated pinocytotic vesicles and microtubules appear topographically related to lysosomes (Fig. 6). Coated pits and clathrin-coated vesicles are also seen.

These electron microscopic findings suggest that endothelial vesicular transport can be discriminated between abluminally orientated transendothelial transport toward the capillary basement membrane inducing oedema formation, and cell organelle orientated intraendothelial vesicular transport directed towards Golgi complex, lysosomes and multivesicular bodies for oedema resolution [8]. Van Deurs [58] has also shown evidence of transport of exogenous material to lysosomes by uncoated endothelial vesicles to be degraded by hydrolytic enzymes.

Numerous free and abluminal membrane-bound pinocytotic vesicles and vacuoles are also found discharging their content into the capillary basement membrane, suggesting the orientated increased pino­cytotic and vacuolar transport toward the tissue front (Fig. 7). These capillaries display notably oedematous pericytes also with an increased vesicular and vacuolar transport [9,18], and swollen glycogen-rich

and glycogen-depleted astrocytic perivascular end-feet [14], indicating the route followed by the hematogenous oedema fluid.

Some endothelial vacuoles are formed by a well-known mechanism of emission of microvilli, which initially projects towards the capillary lumen and afterwards refolds over the neighbouring endothelial luminal surface, or either by interdigitation of a pseudopodic expansion and a microvillus [5,6] (Fig. 8).

In relationship to the identification of endothelial vacuoles, much confusion has been caused in electron microscopy by ultrathin sections of simple indentations of endothelial cell plasma membrane of peripheral cytoplasmic zone, by phagocytosis, and by dilated endoplasmic reticulum [5]. In our studies we have clearly differentiated between these possibilities, and considered that unidirectional transendothelial passage of true protein-containing vacuoles is primarily concerned with oedema formation [6,8].

In some capillaries, the cytoplasm of the endothelial peripheral zone becomes so attenuated that a large micropinocytotic vesicle and vacuoles can function almost as incomplete and transient transendothelial channels [6] (Fig. 9).

Earlier studies on experimental brain trauma have demonstrated that protein leakage occurs as early

as three (3) minutes after brain injury [48]. In addition, plasma protein extravasation has been reported ten minutes after impact injury in spinal gray matter microvasculature [31]. In traumatic human brain in­juries we have shown evidence that there is an accumulation of proteinaceous oedema fluid in the interspace between the basement membrane and the astrocytary perivascular end-feet twenty four (24) hours after a severe brain injury [8,11-13]. Extravasation of proteinaceous oedema fluid in moderately oedematous regions is mainly due to the enhanced vesicular and vacuolar transport because most tight endothelial junctions are intact and structurally closed [8,22].

Concluding remarks

The endothelial vacuolar and vesicular transports have been studied in traumatic brain injuries in order to establish their role in both oedema formation and oedema resolution. Normal or “non-activated” and “activated” capillaries are found. The activated capillaries show predominantly an enhanced abluminally orientated vesicular transport by means of small, medium and large uncoated and clathrin-coated vesicles, as well as the presence of endothelial tubular structures. Vesicles internalizing to the hypertrophic Golgi complex, lysosomes and multivesicular bodies are observed for oedema resolution. The vacuolar transport is predominant in most cortical capillaries.

The basic endothelial cell mechanisms found in complicated human brain injuries are deep invaginations of luminal surface, formation of large coated vesicles, tubular structures, and transient and incomplete trans­endothelial channels formed either by chained plasmalemmal vesicles or elongated protein-containing vacuoles. Uncoated vesicles are seen surrounding lysosomes. The endothelial vesicular transport can be discriminated between abluminally orientated or transendothelial transport (oedema formation), and intraendothelial transport (oedema resolution) directed towards multivesicular bodies and lysosomes.

The transendothelial passage via large vacuoles is mainly due to protein transport. Most endothelial junctions examined in moderate oedematous regions are structurally intact.

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