Microsurgical anatomy of the subcallosal artery.

BACKGROUND AND PURPOSE: The subcallosal artery [SCA, a branch of the anterior communicating artery (ACoA)] is not well described in the literature. However, the memory disorders that can occur after surgical repair of ruptured ACoA aneurysms might be related to infarction of the SCA. The objective of the present study was to perform a thorough anatomical assessment of the SCA. METHODS: The study was carried out over a 6-month period in a University Hospital's anatomy laboratory, using brains extracted from human cadavers. The brains were injected with colored neoprene latex and dissected to study the SCA's origin, path, termination, diameter, length, and vascularized territories. RESULTS: 21 cadaveric specimens were studied. The mean ± standard deviation diameter and length of the SCA were 0.83 ± 0.57 mm and 38.14 ± 25.11 mm, respectively. The predominantly vascularized territories were the paraterminal gyrus (100%), the parolfactory gyrus (78.95%), the rostrum (84.21%) and genu (78.95%) of the corpus callosum, the lamina terminalis (78.95%), the anterior commissure (63.16%), the anterior cingulate gyrus (47.37%), and the fornix (26.32%). When the SCA supplied the fornix and the anterior cingulate gyrus, it was significantly longer and broader (p < 0.05). CONCLUSION: Anatomic knowledge of the SCA is crucial-especially for the treatment of ACoA aneurysms.

Neural deletion of Tgfbr2 impairs angiogenesis through an altered secretome.

Simultaneous generation of neural cells and that of the nutrient-supplying vasculature during brain development is called neurovascular coupling. We report on a transgenic mouse with impaired transforming growth factor ß (TGFß)-signalling in forebrain-derived neural cells using a Foxg1-cre knock-in to drive the conditional knock-out of the Tgfbr2. Although the expression of FOXG1 is assigned to neural progenitors and neurons of the telencephalon, Foxg1(cre/+);Tgfbr2(flox/flox) (Tgfbr2-cKO) mutants displayed intracerebral haemorrhage. Blood vessels exhibited an atypical, clustered appearance were less in number and displayed reduced branching. Vascular endothelial growth factor (VEGF) A, insulin-like growth factor (IGF) 1, IGF2, TGFß, inhibitor of DNA binding (ID) 1, thrombospondin (THBS) 2, and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) 1 were altered in either expression levels or tissue distribution. Accordingly, human umbilical vein endothelial cells (HUVEC) displayed branching defects after stimulation with conditioned medium (CM) that was derived from primary neural cultures of the ventral and dorsal telencephalon of Tgfbr2-cKO. Supplementing CM of Tgfbr2-cKO with VEGFA rescued these defects, but application of TGFß aggravated them. HUVEC showed reduced migration towards CM of mutants compared with controls. Supplementing the CM with growth factors VEGFA, fibroblast growth factor (FGF) 2 and IGF1 partially restored HUVEC migration. In contrast, TGFß supplementation further impaired migration of HUVEC. We observed differences along the dorso-ventral axis of the telencephalon with regard to the impact of these factors on the phenotype. Together these data establish a TGFBR2-dependent molecular crosstalk between neural and endothelial cells during brain vessel development. These findings will be useful to further elucidate neurovascular interaction in general and to understand pathologies of the blood vessel system such as intracerebral haemorrhages, hereditary haemorrhagic telangiectasia, Alzheimers disease, cerebral amyloid angiopathy or tumour biology.

Foxc1 is required for early stage telencephalic vascular development.

BACKGROUND: The brain vascular system arises from the perineural vascular plexus (PNVP) which sprouts radially into the neuroepithelium and subsequently branches off laterally to form a secondary plexus in the subventricular zone (SVZ), the subventricular vascular plexus (SVP). The process of SVP formation remains to be fully elucidated. We investigated the role of Foxc1 in early stage vascular formation in the ventral telencephalon. RESULTS: The Foxc1 loss of function mutant mouse, Foxc1(ch/ch) , showed enlarged telencephalon and hemorrhaging in the ventral telencephalon by embryonic day 11.0. The mutant demonstrated blood vessel dilation and aggregation of endothelial cells in the SVZ after the invasion of endothelial cells through the radial path, which lead to failure of SVP formation. During this early stage of vascular development, Foxc1 was expressed in endothelial cells and pericytes, as well as in cranial mesenchyme surrounding the neural tube. Correspondingly, abnormal deposition pattern of basement membrane proteins around the vessels and increased strong Vegfr2 staining dots were found in the aggregation sites. CONCLUSIONS: These observations reveal an essential role for Foxc1 in the early stage of vascular formation in the telencephalon.

[Reactive changes of the rat brain cellular elements under different conditions of circulatory hypoxia].

The aim of this study was to detect structural, spatial and quantitative changes of cellular elements of midbrain paranigral nucleus (PNN) and telencephalic anterior cingulate area (ACA) under different conditions of circulatory hypoxia. PNN anteriormedial part and ACA layers V-VI were examined in adult rats 7 days (n=4) after an occlusion of both common carotid arteries as well as in intact (1st control, n=4) and sham-operated animals (2nd control, n=4). In histological the sections, stained with Nissl cresyl violet, and using the methods of glial fibrillary acidic protein and an Ibal-protein detection, the proportions of unmodified, hypochromic, pyknomorphic neurons and ghost cells were determined as well as the numbers of astrocytes, oligodendrocytes, microgliocytes and endotheliocytes. Cell body area of neurons and gliocytes, and the distance between cell bodies and capillaries were measured, a gliocyte-neuronal index was calculated. It was found that brain cellular elements that survive different conditions of a circulatory hypoxia underwent a range of pathological changes. Neurons were in process of nuclear pyknosis, lysis and transformation into the ghost cells. The cells within the hypoxia nuclear zone were prone to death or pyknosis. The neurons located outside the area of hypoxia which were affected only by a humoral impact of reactions of the glutamate-calcium cascade, frequently underwent acute swelling. Microgliocyte reaction in the form of poorly expressed increase in their number and structural signs of activation was an early diffuse manifestation of a prosencephalic focal hypoxia. Endotheliocyte proliferation 7 days after of ischemic challenge was not associated with a chain of cascade reactions and was observed only in the hypoxia focus. Concentration of viable neurons and astrocytes near blood capillaries, as well as an increase in the number of satellite form gliocytes is an adaptation mechanism and a condition for the survival of cells during various types of brain exposure to ischemia.

Penetration and differentiation of cephalic neural crest-derived cells in the developing mouse telencephalon.

Neural crest (NC) cells originate from the neural folds and migrate into the various embryonic regions where they differentiate into multiple cell types. A population of cephalic neural crest-derived cells (NCDCs) penetrates back into the developing forebrain to differentiate into microvascular pericytes, but little is known about when and how cephalic NCDCs invade the telencephalon and differentiate into pericytes. Using a transgenic mouse line in which NCDCs are genetically labeled with enhanced green fluorescent protein (EGFP), we observed that NCDCs started to invade the telencephalon together with endothelial cells from embryonic day (E) 9.5. A majority of NCDCs located in the telencephalon expressed pericyte markers, that is, PDGFRß and NG2, and differentiated into pericytes around E11.5. Surprisingly, many of the NC-derived pericytes express p75, an undifferentiated NCDC marker at E11.5, as well as NCDCs in the mesenchyme. At the same time, a minor population of NCDCs that located separately from blood vessels in the telencephalon were NG2-negative and some of these NCDCs also expressed p75. Proliferation and differentiation of pericytes appeared to occur in a specific mesenchymal region where blood vessels penetrated into the telencephalon. These results indicate that (i) NCDCs penetrate back into the telencephalon in parallel with angiogenesis, (ii) many NC-derived pericytes may be still in pre-mature states even though after differentiation into pericytes in the early developing stages, (iii) a small minority of NCDCs may retain undifferentiated states in the developing telencephalon, and (iv) a majority of NCDCs proliferate and differentiate into pericytes in the mesenchyme around the telencephalon.

Angiopoietin-2 regulates cortical neurogenesis in the developing telencephalon.

Vascular-specific growth factor angiopoietin-2 (Ang2) is mainly involved during vascular network setup. Recently, Ang2 was suggested to play a role in adult neurogenesis, affecting migration and differentiation of adult neuroblasts in vitro. However, to date, no data have reported an effect of Ang2 on neurogenesis during embryonic development. As we detected Ang2 expression in the developing cerebral cortex at embryonic day E14.5 and E16.5, we used in utero electroporation to knock down Ang2 expression in neuronal progenitors located in the cortical ventricular zone (VZ) to examine the role of Ang2 in cortical embryonic neurogenesis. Using this strategy, we showed that radial migration from the VZ toward the cortical plate of Ang2-knocked down neurons is altered as well as their morphology. In parallel, we observed a perturbation of intermediate progenitor population and the surrounding vasculature. Taken together, our results show for the first time that, in addition to its role during brain vasculature setup, Ang2 is also involved in embryonic cortical neurogenesis and especially in the radial migration of projection neurons.

Compartment-specific transcription factors orchestrate angiogenesis gradients in the embryonic brain.

Prevailing notions of cerebral vascularization imply that blood vessels sprout passively into the brain parenchyma from pial vascular plexuses to meet metabolic needs of growing neuronal populations. Endothelial cells, building blocks of blood vessels, are thought to be homogeneous in the brain with respect to their origins, gene expression patterns and developmental mechanisms. These current notions that cerebral angiogenesis is regulated by local environmental signals contrast with current models of cell-autonomous regulation of neuronal development. Here we demonstrate that telencephalic angiogenesis in mice progresses in an orderly, ventral-to-dorsal gradient regulated by compartment-specific homeobox transcription factors. Our data offer new perspectives on intrinsic regulation of angiogenesis in the embryonic telencephalon, call for a revision of the current models of telencephalic angiogenesis and support novel roles for endothelial cells in brain development.

Intact in vivo visualization of telencephalic microvasculature in medaka using optical coherence tomography.

To date, various human disease models in small fish-such as medaka (Oryzias lapties)-have been developed for medical and pharmacological studies. Although genetic and environmental homogeneities exist, disease progressions can show large individual differences in animal models. In this study, we established an intact in vivo angiographic approach and explored vascular networks in the telencephalon of wild-type adult medaka using the spectral-domain optical coherence tomography. Our approach, which required neither surgical operations nor labeling agents, allowed to visualize blood vessels in medaka telencephala as small as about 8 µm, that is, almost the size of the blood cells of medaka. Besides, we could show the three-dimensional microvascular distribution in the medaka telencephalon. Therefore, the intact in vivo imaging via optical coherence tomography can be used to perform follow-up studies on cerebrovascular alterations in metabolic syndrome and their associations with neurodegenerative disease models in medaka.

Reciprocal Interaction between Vascular Filopodia and Neural Stem Cells Shapes Neurogenesis in the Ventral Telencephalon.

Angiogenesis and neurogenesis are tightly coupled during embryonic brain development. However, little is known about how these two processes interact. We show that nascent blood vessels actively contact dividing neural stem cells by endothelial filopodia in the ventricular zone (VZ) of the murine ventral telencephalon; this association is conserved in the human ventral VZ. Using mouse mutants with altered vascular filopodia density, we show that this interaction leads to prolonged cell cycle of apical neural progenitors (ANPs) and favors early neuronal differentiation. Interestingly, pharmacological experiments reveal that ANPs induce vascular filopodia formation by upregulating vascular endothelial growth factor (VEGF)-A in a cell-cycle-dependent manner. This mutual relationship between vascular filopodia and ANPs works as a self-regulatory system that senses ANP proliferation rates and rapidly adjusts neuronal production levels. Our findings indicate a function of vascular filopodia in fine-tuning neural stem cell behavior, which is the basis for proper brain development.

Neuropathic and cerebrovascular correlates of hearing loss in Fabry disease.

Fabry disease, OMIM 301500, is a progressive multisystem storage disorder due to the deficiency of alpha-galactosidase A (GALA). Neurological and vascular manifestations of this disorder with regard to hearing loss have not been analysed quantitatively in large cohorts. We conducted a retrospective cross sectional analysis of hearing loss in 109 male and female patients with Fabry disease who were referred to and seen at the Clinical Center of the National Institutes of Health, Bethesda, MD, USA on natural history and enzyme replacement study protocols. There were 85 males aged 6-58 years (mean 31 years, SD 13) and 24 females aged 22-72 years (mean 42 years, SD 12). All patients underwent a comprehensive audiological evaluation. In addition, cerebral white matter lesions, peripheral neuropathy, and kidney function were quantitatively assessed. HL(95), defined as a hearing threshold above the 95th percentile for age and gender matched normal controls, was present in 56% [95% CI (42.2-67.2)] of the males. Prevalence of HL(95) was lower in the group of patients with residual GALA enzyme activity compared with those without detectable activity (33% versus 63%) HL(95) was present in the low-, mid- and high-frequency ranges for all ages. Male patients with HL(95) had a higher microvascular cerebral white matter lesion load [1.4, interquartile range (IQR) 0-30.1 +/- versus 0, IQR 0-0], more pronounced cold perception deficit [19.4 +/- 5.5 versus 13.5 +/- 5.5 of just noticeable difference (JND) units] and lower kidney function [creatinine: 1.6 +/- 1.2 versus 0.77 +/- 0.2 mg/dl; blood urea nitrogen (BUN): 20.1 +/- 14.1 versus 10.3 +/- 3.28 mg/dl] than those without HL(95) (P < 0.001). Of the females, 38% had HL(95). There was no significant association with cold perception deficit, creatinine or BUN in the females. Word recognition and acoustic reflexes analyses suggested a predominant cochlear involvement. We conclude that hearing loss involving all frequency regions significantly contributes to morbidity in patients with Fabry disease. Our quantitative analysis suggests a correlation of neuropathic and vascular damage with hearing loss in the males. Residual GALA activity appears to have a protective effect against hearing loss.

Long-term neuroblast migration along blood vessels in an area with transient angiogenesis and increased vascularization after stroke.

BACKGROUND AND PURPOSE: Stroke induced by middle cerebral artery occlusion (MCAO) causes long-term formation of new striatal neurons from stem/progenitor cells in the subventricular zone (SVZ). We explored whether MCAO leads to hypoxia, changes in vessel density, and angiogenesis in the ipsilateral SVZ and adjacent striatum, and determined the relation between the migrating neuroblasts and the vasculature. METHODS: Adult rats were subjected to 2 hours of MCAO. Hypoxia was studied by injecting Hypoxyprobe-1 during MCAO or 6 weeks later. Vessel density and length was estimated using stereology. New cells were labeled with 5'-bromo-2'deoxyuridine (BrdU) during weeks 1 and 2 or 7 and 8 after MCAO, and angiogenesis was assessed immunohistochemically with antibodies against BrdU and endothelial cell markers. Distance from neuroblasts to nearest vessel was measured using confocal microscopy. RESULTS: The ischemic insult caused transient hypoxia and early, low-grade angiogenesis, but no damage or increase of vascular density in the SVZ. Angiogenesis was detected during the first 2 weeks in the dorsomedial striatum adjacent to the SVZ, which also showed long-lasting increase of vascularization. At 2, 6, and 16 weeks after MCAO, the majority of neuroblasts migrated through this area toward the damage, closely associated with blood vessels. CONCLUSIONS: The vasculature plays an important role for long-term striatal neurogenesis after stroke. During several months, neuroblasts migrate close to blood vessels through an area exhibiting early vascular remodeling and persistently increased vessel density. Optimizing vascularization should be an important strategy to promote neurogenesis and repair after stroke.

Dynamic inositol trisphosphate-mediated calcium signals within astrocytic endfeet underlie vasodilation of cerebral arterioles.

Active neurons communicate to intracerebral arterioles in part through an elevation of cytosolic Ca(2+) concentration ([Ca(2+)](i)) in astrocytes, leading to the generation of vasoactive signals involved in neurovascular coupling. In particular, [Ca(2+)](i) increases in astrocytic processes ("endfeet"), which encase cerebral arterioles, have been shown to result in vasodilation of arterioles in vivo. However, the spatial and temporal properties of endfoot [Ca(2+)](i) signals have not been characterized, and information regarding the mechanism by which these signals arise is lacking. [Ca(2+)](i) signaling in astrocytic endfeet was measured with high spatiotemporal resolution in cortical brain slices, using a fluorescent Ca(2+) indicator and confocal microscopy. Increases in endfoot [Ca(2+)](i) preceded vasodilation of arterioles within cortical slices, as detected by simultaneous measurement of endfoot [Ca(2+)](i) and vascular diameter. Neuronal activity-evoked elevation of endfoot [Ca(2+)](i) was reduced by inhibition of inositol 1,4,5-trisphosphate (InsP(3)) receptor Ca(2+) release channels and almost completely abolished by inhibition of endoplasmic reticulum Ca(2+) uptake. To probe the Ca(2+) release mechanisms present within endfeet, spatially restricted flash photolysis of caged InsP(3) was utilized to liberate InsP(3) directly within endfeet. This maneuver generated large amplitude [Ca(2+)](i) increases within endfeet that were spatially restricted to this region of the astrocyte. These InsP(3)-induced [Ca(2+)](i) increases were sensitive to depletion of the intracellular Ca(2+) store, but not to ryanodine, suggesting that Ca(2+)-induced Ca(2+) release from ryanodine receptors does not contribute to the generation of endfoot [Ca(2+)](i) signals. Neuronally evoked increases in astrocytic [Ca(2+)](i) propagated through perivascular astrocytic processes and endfeet as multiple, distinct [Ca(2+)](i) waves and exhibited a high degree of spatial heterogeneity. Regenerative Ca(2+) release processes within the endfeet were evident, as were localized regions of Ca(2+) release, and treatment of slices with the vasoactive neuropeptides somatostatin and vasoactive intestinal peptide was capable of inducing endfoot [Ca(2+)](i) increases, suggesting the potential for signaling between local interneurons and astrocytic endfeet in the cortex. Furthermore, photorelease of InsP(3) within individual endfeet resulted in a local vasodilation of adjacent arterioles, supporting the concept that astrocytic endfeet function as local "vasoregulatory units" by translating information from active neurons into complex InsP(3)-mediated Ca(2+) release signals that modulate arteriolar diameter.

Expression of angiogenic and neurotrophic factors in the progenitor cell niche of adult monkey subventricular zone.

The subventricular zone along the anterior horn (SVZa) of the cerebral lateral ventricle of adult mammals contains multipotent progenitor cells, which supposedly exist in an angiogenic niche. Numerous signals are known to modulate the precursor cell proliferation, migration or differentiation, in rodent models. In contrast, the data on signals regulating the primate SVZa precursors in vivo are scarce. We analyzed the expression at protein level of a panel of angiogenic and/or neurotrophic factors and their receptors in SVZa of adult macaque monkeys, under normal condition or after transient global ischemia which enhances endogenous progenitor cell proliferation. We found that fms-like tyrosine kinase 1 (Flt1), a receptor for vascular endothelial cell growth factor, was expressed by over 30% of the proliferating progenitors, and the number of Flt1-positive precursors was significantly increased by the ischemic insult. Smaller fractions of mitotic progenitors were positive for the neurotrophin receptor tropomyosin-related kinase (Trk) B or the hematopoietic receptor Kit, while immature neurons expressed Flt1 and the neurotrophin receptor TrkA. Further, SVZa astroglia, ependymal cells and blood vessels were positive for distinctive sets of ligands/receptors, which we characterized. The presented data provide a molecular phenotypic analysis of cell types comprising adult monkey SVZa, and suggest that a complex network of angiogenic/neurotrophic signals operating in an autocrine or paracrine manner may regulate SVZa neurogenesis in the adult primate brain.

Permanent brain ischemia induces marked increments in hsp72 expression and local protein synthesis in synapses of the ischemic hemisphere.

Transient focal ischemia induced in rat brain by occlusion of the middle cerebral artery (MCAo) elicits a generalized induction of the 72 kDa heat-shock protein (hsp72) heralding functional recovery. As this effect implies activation of protein synthesis, and local systems of protein synthesis are present in brain synapses, and may be analyzed in preparations of brain synaptosomes, we evaluated hsp72 expression and protein synthesis in synaptosomal fractions of spontaneously hypertensive rats (SHRs) subjected to permanent MCAo. SHRs were randomly divided in ischemics and sham controls, anaesthesia controls and passive controls. Focal ischemia was induced under chloral hydrate anaesthesia by unilateral permanent MCAo. Protein synthesis was determined by [35S]methionine incorporation into synaptosomal proteins from ischemic and contralateral cortex/striatum, and from cerebellum. Hsp72 expression was measured in the same fractions by immunoblotting. Our data demonstrate that under these conditions synaptic hsp72 markedly increases in the ischemic hemisphere 1 and 2 days after MCAo, progressively declining in the following 2 days, while no significant change occurs in control rats. In addition, in the ischemic hemisphere the rate of synaptic protein synthesis increases more than two-fold between 1 and 4 days after MCAo, without showing signs of an impending decline. The present data provide the first demonstration that synaptic protein synthesis is massively involved in brain plastic events elicited by permanent focal ischemia.

Dexamethasone treatment modulates aquaporin-4 expression after intracerebral hemorrhage in rats.

This study investigated whether dexamethasone (DEX) treatment could regulate the expression of aquaporin-4 (AQP4) in rats with intracerebral hemorrhage (ICH). The results demonstrated that DEX significantly reduced AQP4 mRNA level in the perihematomal area compared with control group, but it increased the level in the brain area surrounding the third ventricle at day 1 post-ICH. There was no difference in AQP4 protein levels between DEX group and control group at the two above-mentioned brain regions at day 1 after ICH. The changes in AQP4 protein induced by DEX were marked at day 3 following surgery and still lasted at day 5 post-ICH, which were accompanied by a reduction of brain edema. Our results demonstrated that the expression of AQP4 protein after ICH was region-specific, time-dependent, and also indicated that DEX-induced cerebral edema clearance was correlated with the regulation of AQP4 expression in different brain regions.

Topographical distribution of cerebral amyloid angiopathy and its effect on cognitive decline are influenced by Alzheimer disease pathology.

Cerebral amyloid angiopathy (CAA) is defined by beta-amyloid peptide (Abeta) depositions in cerebral vessels and is associated with Alzheimer disease (AD). It has been suggested that severe CAA is an independent risk factor for cognitive decline. 171 autopsy brains underwent standardized neuropathological assessment, the patients age ranged from 54 to 104 years (mean age: 83.9 years, +/-9.2, 59.6% female, 56.1% clinically demented). Using immunohistochemistry, the severity of Abeta depositions in vessels was assessed semiquantitatively in the frontal, frontobasal, hippocampal, and occipital region, respectively. CAA was present in 117 cases (68.4%), with the occipital region being affected significantly stronger than other regions. The overall incidence of CAA was significantly higher in cases with high grade neuritic AD pathology (ADP) compared to those with low grade or no ADP. The severity of CAA significantly increased with increasing ADP, with CAA in the occipital region increasing significantly stronger than that in other regions. The association of CAA and clinical dementia failed to remain statistically significant when adjusting for concomitant ADP. However, in cases devoid of any ADP CAA was significantly associated with the presence of clinical dementia. These results indicate a strong association of AD with CAA, but do not unequivocally support reports suggesting CAA to be an independent risk factor for cognitive decline, except for a subgroup of demented patients lacking any ADP.

Does EEG (visual and quantitative) reflect mental impairment in subcortical vascular dementia?

UNLABELLED: The aim of this study was to determine if the results of visual and quantitative EEG (QEEG) parameters reveal a correlation with mental impairment in subcortical vascular dementia (SVD), one of the most frequent causes of cognitive impairment in the elderly. In SVD, like in Alzheimer's disease disturbances were found in cholinergic transmission. The cholinergic deficit as manifested in changes of synaptic potentials is reflected in EEG signals. MATERIAL: 31 patients with probable SVD (according to NINCDS-AIREN and T. Erkinjuntii's criteria) and mean age 72.3 yrs;(M--43%, F--57%) and 14 healthy control subjects with mean age of 72.3 yrs (M-57%, F-43%). According to the Mini Mental Scale Examination (MMSE) the SVD group was divided into two subgroups with mild and moderate dementia, their EEGs being recorded with a Medelec and Neuroscan 4.2 system. Visual EEG findings were classified with the use of eight-degree scale of pathological changes by the presence of slow waves. Then QEEGs were made. The following parameters were calculated: alpha/slow wave power ratios, the mean wave frequency in all and in some selected derivations. RESULTS: A significant difference was found between QEEGs in SVD subgroups with mild and moderate dementia (p<0.05), but there was no significant difference between visual EEGs. A significant correlation between QEEG parameters such as alpha/slow wave ratio or mean wave frequency and mental impairment (according to MMSE results) was found (p<0.001), but there was no significant correlation between degree of EEG abnormalities in visual analysis and MMSE results. CONCLUSION: Only QEEGs are correlated with mental impairment in SVD. Visual EEG technique as a less precise tool does not reflect the mental impairment in SVD due to cholinergic deficit.

Defective associations between blood vessels and brain parenchyma lead to cerebral hemorrhage in mice lacking alphav integrins.

Mouse embryos genetically null for the alphav integrin subunit develop intracerebral hemorrhages at midgestation and die shortly after birth. A key question is whether the hemorrhage arises from primary defects in vascular endothelial cells or pericytes or from other causes. We have previously reported normal initiation of cerebral vessels comprising branched tubes of endothelial cells. Here we show that the onset of hemorrhage is not due to defects in pericyte recruitment. Additionally, most alphav-null vessels display ultrastructurally normal endothelium-pericyte associations and normal interendothelial cell junctions. Thus, endothelial cells and pericytes appear to establish their normal relationships in cerebral microvessels. However, by both light and electron microscopy, we detected defective associations between cerebral microvessels and the surrounding brain parenchyma, composed of neuroepithelial cells, glia, and neuronal precursors. These data suggest a novel role for alphav integrins in the association between cerebral microvessels and central nervous system parenchymal cells.

The comparative effects of intravenous nicardipine and prostaglandin E1 on the cerebral pial arteriolar constriction seen after unclamping of an aortic cross-clamp in rabbits.

BACKGROUND: The potent vasodilators nicardipine and prostaglandin E1 (PGE1) are useful for the treatment of systemic hypertension or pulmonary hypertension during aortic surgery. METHODS: We measured cerebral pial arteriolar diameters, using a rabbit closed cranial window preparation: before (baseline) and 15 min after the start of an IV infusion (preclamp) (0.9% saline [control group], nicardipine [at 0.1, 1.0, or 10 microg x kg(-1) x min(-1)], or PGE1 [at 0.1 or 1.0 microg x kg(-1) x min(-1)]), just after aortic clamping, 20 min after clamping, and at 0-60 min after unclamping. RESULTS: In the control group, a significant decrease in diameter persisted for at least 60 min after unclamping (maximum [at 60 min], -16% for large [> or =75 microm], and -27% for small [<75 microm] arterioles versus baseline). Although the aortic unclamping-induced vasoconstriction was unaffected under the smallest dose of nicardipine, it was significantly attenuated under larger doses in both large and small arterioles (residual vasoconstriction, -10% and -6% for large and -18% and -10% for small arterioles; at 60 min). The pial arteriolar constriction observed at 5 min or more after unclamping in the control group was not altered by PGE1 in either large or small arterioles. CONCLUSIONS: The larger doses of nicardipine, but neither dose of PGE1, attenuated aortic unclamping-induced sustained cerebral pial arteriolar constriction.

Intracerebral regional distribution of blood flow in response to uterine contractions in growth-restricted human fetuses.

OBJECTIVE: To explore middle cerebral artery (MCA) and anterior cerebral artery (ACA) blood flow responses to superimposed acute hypoxemia in growth-restricted fetuses with and without established brain-sparing flow during basal conditions. MATERIAL AND METHODS: 47 term fetuses suspected of growth restriction were exposed to an oxytocin challenge test with simultaneous cardiotocography and Doppler velocimetry in the umbilical artery, MCA and ACA. The MCA-to-ACA pulsatility index (PI) ratio was calculated during basal conditions, contractions and relaxations. Basal brain-sparing flow was defined as an MCA-to-umbilical artery PI ratio of<1.08, de novo brain-sparing flow in the MCA as an MCA PI decrease with> or =1 standard deviation during uterine contractions or relaxations compared with basal measurements, and de novo brain-sparing flow in the ACA as an ACA PI decrease with > or =1 standard deviation. Non-parametric statistical tests were used with P<0.05 considered significant. RESULTS: MCA and ACA PI were both significantly lower in the brain-sparing flow group (N=8) during basal conditions (P< or =0.01). During the oxytocin challenge test, MCA and ACA PI both decreased in the non-brain-sparing flow group (N=39) (P< or =0.02) but not in the brain-sparing flow group (P> or =0.4). The MCA-to-ACA PI ratio remained unchanged in both groups. de novo brain-sparing flow calculations revealed no preferential flow to any cerebral artery. CONCLUSION: Cerebral circulatory responses to acute hypoxemia are synchronized in the middle and anterior cerebral arteries without any preferential regional flow distribution.