Microcirculation

Abstract: Reperfusion of ischaemic tissues is often associated with microvascular dysfunction that is manifested as impaired endothelium-dependent dilation in arterioles, enhanced fluid filtration and leukocyte plugging in capillaries, and the trafficking of leukocytes and plasma protein extravasation in postcapillary venules Activated endothelial cells in all segments of the microcirculation produce more oxygen radicals, but less nitric oxide, in the initial period following reperfusion The resulting imbalance between superoxide and nitric oxide in endothelial cells leads to the production and release of inflammatory mediators (eg platelet-activating factor, tumour necrosis factor) and enhances the biosynthesis of adhesion molecules that mediate leukocyte-endothelial cell adhesion Some of the known risk factors for cardiovascular disease (hypercholesterolaemia, hypertension, and diabetes) appear to exaggerate many of the microvascular alterations elicited by ischaemia and reperfusion (I/R) The inflammatory mediators released as a consequence of reperfusion also appear to activate endothelial cells in remote organs that are not exposed to the initial ischaemic insult This distant response to I/R can result in leukocyte-dependent microvascular injury that is characteristic of the multiple organ dysfunction syndrome Adaptational responses to I/R injury have been demonstrated that allow for protection of briefly ischaemic tissues against the harmful effects of subsequent, prolonged ischaemia, a phenomenon called ischaemic preconditioning There are two temporally and mechanistically distinct types of protection afforded by this adaptational response, ie acute and delayed preconditioning The factors (eg protein kinase C activation) that initiate the acute and delayed preconditioning responses appear to be similar; however the protective effects of acute preconditioning are protein synthesis-independent, while the effects of delayed preconditioning require protein synthesis The published literature in this field of investigation suggests that there are several potential targets for therapeutic intervention against I/R-induced microvascular injury

Abstract: Increases in brain blood flow, evoked by neuronal activity, power neural computation and form the basis of BOLD (blood-oxygen-level-dependent) functional imaging. Whether blood flow is controlled solely by arteriole smooth muscle, or also by capillary pericytes, is controversial. We demonstrate that neuronal activity and the neurotransmitter glutamate evoke the release of messengers that dilate capillaries by actively relaxing pericytes. Dilation is mediated by prostaglandin E2, but requires nitric oxide release to suppress vasoconstricting 20-HETE synthesis. In vivo, when sensory input increases blood flow, capillaries dilate before arterioles and are estimated to produce 84% of the blood flow increase. In pathology, ischaemia evokes capillary constriction by pericytes. We show that this is followed by pericyte death in rigor, which may irreversibly constrict capillaries and damage the blood-brain barrier. Thus, pericytes are major regulators of cerebral blood flow and initiators of functional imaging signals. Prevention of pericyte constriction and death may reduce the long-lasting blood flow decrease that damages neurons after stroke.

Abstract: The highly impermeable tight junctions between endothelial cells forming the capillaries and venules in the central nervous system (CNS) of higher vertebrates are thought to be responsible for the blood-brain barrier that impedes the passive diffusion of solutes from the blood into the extracellular space of the CNS. The ability of CNS endothelial cells to form a blood-brain barrier is not intrinsic to these cells but instead is induced by the CNS environment: Stewart and Wiley demonstrated that when avascular tissue from 3-day-old quail brain is transplanted into the coelomic cavity of chick embryos, the chick endothelial cells that vascularize the quail brain grafts form a competent blood-brain barrier; on the other hand, when avascular embryonic quail coelomic grafts are transplanted into embryonic chick brain, the chick endothelial cells that invade the mesenchymal tissue grafts form leaky capillaries and venules. It is, however, not known which cells in the CNS are responsible for inducing endothelial cells to form the tight junctions characteristic of the blood-brain barrier. Astrocytes are the most likely candidates since their processes form endfeet that collectively surround CNS microvessels. In this report we provide direct evidence that astrocytes are capable of inducing blood-brain barrier properties in non-neural endothelial cells in vivo.

Abstract: Blood flow rate in a vascular network is proportional to the pressure difference between the arterial and venous sides and inversely proportional to the viscous and geometric resistances. Despite rapid progress in recent years, there is a paucity of quantitative data on these three determinants of blood flow in tumors and several questions remain unanswered. This paper reviews our current knowledge of these three parameters for normal and neoplastic tissues, the methods of their measurements, and the implications of the results in the growth and metastasis formation as well as in the detection and treatment of tumors. Microvascular pressures in the arterial side are nearly equal in tumor and nontumorous vessels. Pressures in venular vessels, which are numerically dominant in tumors, are significantly lower in a tumor than those in a nontumorous tissue. Decreased intravascular pressure and increased interstitial pressure in tumors are partly responsible for the vessel collapse as well as the flow stasis and reversal in tumors. The apparent viscosity (viscous resistance) of blood is governed by the viscosity of plasma and the number, size, and rigidity of blood cells. Plasma viscosity can be increased by adding certain solutes. The concentration of cells can be increased by adding cells to blood or by reducing plasma volume. The rigidity of RBC, which are numerically dominant in blood, can be increased by lowering pH, elevating temperature, increasing extracellular glucose concentration, or making the suspending medium hypo- or hypertonic. Effective size of blood cells can be increased by forming RBC aggregates (also referred to as rouleaux). RBC aggregation can be facilitated by lowering the shear rate (i.e., decreasing velocity gradients) or by adding macromolecules (e.g., fibrinogen, globulins, dextrans). Since cancer cells and WBC are significantly more rigid than RBC, their presence in a vessel may also increase blood viscosity and may even cause transient stasis. Finally, due to the relatively large diameters of tumor microvessels the Fahraeus effect (i.e., reduction in hematocrit in small vessels) and the Fahraeus-Lindqvist effect (i.e., reduction in blood viscosity in small vessels) may be less pronounced in tumors than in normal tissues. Geometric resistance for a network of vessels is a complex function of the vascular morphology, i.e., the number of vessels of various types, their branching pattern, and their length and diameter. Geometric resistance to flow in a single vessel is proportional to the vessel length and inversely proportional to vessel diameter to the fourth power.(ABSTRACT TRUNCATED AT 400 WORDS)