**2. Posthypoxic blood vessel motricity and posthypoxic endothelial dysfunction**

Blood vessels, and especially endothelium located at the blood-organ interface, are partic‐ ularly susceptible to ischemia-reperfusion injuries. Endothelial stunning or the loss of en‐ dothelial functions during reperfusion contributes to IR injuries and compromises the postischemic recovery. [5-7]

The basal vascular tone is a continual balance between vasoconstrictors and vasodilators acting on the blood vessel. Vascular smooth muscle cells (VSMCs) and endothelium play pivotal roles in this control.

© 2013 Gourdin and Dubois; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Posthypoxic vasoconstriction, in response to vasoconstrictors, and endothelium-independ‐ ent vasodilation, induced by direct vasodilators (direct action on VSMCs), are slightly af‐ fected by I/R, demonstrating the relative resistance of VSMCs. [8]-[10] In contrast, endothelium-dependent dilatation is deeply affected. Despite the fact that endothelial cells seem relatively more resistant than other cells types (cardiomyocytes, neurons, renal tubular cell), I/R modifies their phenotype: diminution of their anticoagulant properties, increased vascular permeability, increased leukoadhesivity and establishment of a proin‐ flammatory state in the endovascular milieu.

extend to the whole body and, particularly, the organs with a high capillary density, such as

Reperfusion injury is characterized by autoimmune responses, including natural antibodies recognizing neoantigens and subsequent activation of the complement system (auto-im‐

during ischemia and reperfusion through complement-mediated recognition of damaged cells and anaphylatoxin release. The anaphylatoxins C3a, C4a and C5a lead to the recruit‐ ment and stimulation of immune cells, which promotes cell-cell interactions by increasing the expression of adhesion molecules (vascular cell adhesion molecule-1, ICAM-1, E-selectin and P-selectin) on the surface of the endothelial cells and neutrophils. [12],[39] Moreover, C5a is a chemotactic factor that directly stimulates leukocytes to synthesize and secrete cyto‐ kines such as interleukin (IL)-1, IL-6, monocyte chemoattractant protein-1 (MCP-1) and TNF-α. iC3b is implicated in neutrophil-endothelium interactions. C5b-9, known as the final cytolytic membrane attack complex complement, is a powerful chemotactic agent that caus‐ es direct lesions to the endothelial cells, stimulates the endothelial production of IL-8,

During reperfusion, neutrophils play a central part in the inflammatory response and in the genesis of the I/R injuries. Activated neutrophils produce high amounts of cytokines, che‐ mokines, and ROS in the vascular lumen but also in the parenchyma that directly contacts cells. These neutrophils and endothelial cells activated by cytokines (e.g., IL-6, TNF-α, IL-8, IL-1β) and other proinflammatory mediators (e.g., platelet-activating factor, ROS) promote a close interaction between these cell types that will result in a significant concentration of ac‐ tivated neutrophils in the interstitium. [1],[13],[15],[17],[32],[40]-[43] This complex process can be summarized in four steps: chemoattraction, weak neutrophil adhesion to the endo‐ thelium, followed by a stronger adhesion and, finally, neutrophil migration (Figure 1). Three families of sarcoplasmic adhesion molecules are implicated in the neutrophil-endothelium

Upon reperfusion, the endothelium, parenchyma and resident immune cells (mainly macro‐ phages and neutrophils) release cytokines such as IL-1, TNF-α and chemokines, inducing the production of selectins by endothelial and immune cells. Circulating leukocytes are concen‐

Endothelial L-selectin interacts with the P-selectin and the E-selectin-specific ligand-1 (ESL-1) expressed by neutrophils. [44],[45] The activation of TLR-2, ROS production, the complement

trated towards the site of injury by the concentration gradient of chemokines.

MCP-1, and ROS and inhibits endothelium-dependent vasodilatation. [12],[39]

Locally produced and activated, the complement system amplifies inflammation

Inflammation and Vasomotricity During Reperfusion

http://dx.doi.org/10.5772/54508

21

lung, brain and kidney. [1],[12],[37],[38]

munity). 1

**3.1. Activation of the complement system**

**3.2. Cell-cell interactions during reperfusion**

interaction: selectins, β2-integrins and immunoglobulins.

*3.2.1. Neutrophil–endothelium interaction*

**•** Chemoattraction:

**•** Rolling adhesion

The production of some bioactive agents decreases (e.g., prostacyclin, nitric oxide), while that of others increases during I/R (e.g., endothelin, thromboxane A2). [1],[11]-[16] These endothe‐ lial modifications are called endothelial dysfunction and are widely described in human and animals studies.[15],[17]-[21] IR-related endothelial dysfunction is mainly characterized by the loss of NO availability and seems to be related to the reperfusion more than to ischemia. [10] In normal situations, NO acts in numerous pathways: direct vasodilation, indirect vasodilation by inhibiting the influences of vasoconstrictors (e.g., inhibiting angiotensin II and sympathetic vasoconstriction), inhibiting platelet adhesion to the vascular endothelium (anti-thrombotic effect), inhibiting leukocyte adhesion to vascular endothelium (anti-inflammatory effect), and inhibiting smooth muscle hyperplasia by scavenging superoxide anion (anti-proliferative effect). The diminution of NO concentration jeopardizes these functions.

Multiple hypotheses have been proposed to explain postischemic endothelial dysfunction: massive ROS production by mitochondria, activation of immune cells, activation of xanthine oxidase and NADPH2 oxidase by the ceramide/sphingosine kinase pathway, the depletion of dihydrobiopterin (an essential cofactor of nitric oxide synthase), increased arginine consump‐ tion in other intracellular pathways, the production of chemokines and cytokines (tumor necrosis factor-alpha (TNF-α), interleukin-1, -6, and -8) or the activation of the complement system (C3a fraction, C5b-9 fraction). [21]-[31]

In normoxic conditions, the endothelium permits only restricted diffusion. During hypoxia, the modifications of the cytoskeleton of endothelial cells, induced by hypoxia and low intracellular cyclic adenosine monophosphate phosphate (cAMP) concentration, increase vascular permea‐ bility, leading to capillary leakage and perivascular interstitial edema.[1] Complement system activation, leukocyte endothelial adhesion and platelet-leukocyte aggregation increase after re‐ perfusion.[1],[32] A clinical example is the acute respiratory failure with hypoxia and pulmona‐ ry edema observed in several surgeries. Acute respiratory distress syndrome is caused by heart failure but also by a disruption of the alveolar-capillary barrier.[33]-[36]
