NO and the Homeostasis of the Blood Cell Interaction with the Vessel Wall

Preserving a Nonthrombogenic Surface of the Endothelium

In addition to the role of NO as a vasodilator, NO in the microcirculation can prevent platelets from adhering to the endothelium and can assist with the disaggregation of activated platelets to the endothelium or underlying basement membrane (Figure 1). More recently, this concept was unequivocally demonstrated in mice deficient for eNOS [6, 7]. Bleeding times were decreased in eNOS (-/-) mice and platelet adhesion to venules was increased in response to bacterial lipopolysaccharide (LPS) when a NOS inhibitor was given. Similarly, mice deficient in eNOS, but not iNOS or nNOS, also exhibited increased platelet adhesion. In both instances, eNOS in the endothelium as well as in the platelet per se contributed to the antiplatelet actions of eNOS-derived NO.

Maintaining an Anti-inflammatory State of the Vessel Wall

Inflammation can be described as the physiological response of the microcirculation to injury or infections.

Designed to close off or destroy injured tissue, inflammatory response is hallmarked by increases in leukocyte-endothelium interactions. Recently, NO has emerged as a crucial endogenous anti-inflammatory mediator in a number of pathophysiological states including hypercholes-terolemia and ischemia-reperfusion injury. More specifically, NO can act by downregulating cytokines, resulting in the downregulation of endothelial cell adhesion molecules (ECAMs). The mechanism of leukocyte recruitment is mediated by these ECAMs such as the selectin family (P- and E-selectin), which are important modulators of leukocyte-endothelium interaction via leukocyte rolling along the endothelium and adhesion to the endothelium. Once the cells begin to roll, they can then firmly attach to the endothelium via integrin interaction with endothelial intercellular adhesion molecules (ICAMs) to promote leukocyte adhesion.

Pharmacological studies have shown that NOS inhibitors could increase leukocyte adhesion, an effect that can be reversed by large amounts of exogenous L-arginine. Similar studies using eNOS (-/-) mice confirmed that upon activation of an inflammatory response, eNOS derived NO is critical for reducing leukocytes adhesion and the extent of tissue injury. Recent data suggest that NO is derived from eNOS and nNOS, but interestingly, iNOS may be an endogenous inhibitor of P-selectin. eNOS and nNOS (-/-)

Figure 1 The role of NO in the microcirculation. NO, a gaseous free radical, can exert multiple effects in the microcirculatory bed and is a major player in regulating the cardiovascular system. Studies have shown the vasodilatory effect of NO in large blood vessels as well as in the arterioles and venules. This mainly occurs when NO synthesized by the endothelium diffuses to the surrounding vascular smooth muscle, activating guanylyl cyclase (GC), thereby increasing cytosolic cGMP to produce smooth muscle relaxation. NO can also regulate homeostasis of the blood vessel wall by preventing platelet adhering and disaggregation from the endothelium. Furthermore, NO can negatively regulate leukocyte-endothelium interaction by downregulating cytokines and ECAMs such as P-selectin that are important for leukocyte rolling and adhesion to endothelial cells. Thus, NO serves as an anti-inflammatory mediator in pathological conditions such as hypercholesterolemia or as a car-dioprotectant in myocardial ischemia-reperfusion injuries. In addition, NO is a crucial regulator of microvascu-lar permeability. Controversy exists to whether NO promotes or inhibits basal versus stimulated changes in vascular permeability. (see color insert)

Figure 1 The role of NO in the microcirculation. NO, a gaseous free radical, can exert multiple effects in the microcirculatory bed and is a major player in regulating the cardiovascular system. Studies have shown the vasodilatory effect of NO in large blood vessels as well as in the arterioles and venules. This mainly occurs when NO synthesized by the endothelium diffuses to the surrounding vascular smooth muscle, activating guanylyl cyclase (GC), thereby increasing cytosolic cGMP to produce smooth muscle relaxation. NO can also regulate homeostasis of the blood vessel wall by preventing platelet adhering and disaggregation from the endothelium. Furthermore, NO can negatively regulate leukocyte-endothelium interaction by downregulating cytokines and ECAMs such as P-selectin that are important for leukocyte rolling and adhesion to endothelial cells. Thus, NO serves as an anti-inflammatory mediator in pathological conditions such as hypercholesterolemia or as a car-dioprotectant in myocardial ischemia-reperfusion injuries. In addition, NO is a crucial regulator of microvascu-lar permeability. Controversy exists to whether NO promotes or inhibits basal versus stimulated changes in vascular permeability. (see color insert)

mice exhibited increased expression of P-selectin in their mesenteric venules as well as increased leukocyte rolling and adhesion that can be blocked by both the P-selectin neutralizing antibody and a high-affinity P-selectin ligand [8]. This supports previous findings that NOS inhibition by NOS inhibitors caused a significant increase in P-selectin expression in the postcapillary venules. Using another inflammatory model, namely the myocardial ischemia-reperfusion injury, NO was also shown to provide a protective role in the injury cascade leading to inflammation. In particular, other studies by the Lefer group have shown that eNOS-deficient mice exhibited exacerbated reperfusion injury compared to wild-type mice, an effect associated with upregulated P-selectin expression and enhanced infiltration of neutrophils. Recently, transgenic mice overexpressing eNOS in the endothelium have been generated. In accordance with the findings from eNOS (-/-) mice, overexpression of eNOS in these transgenic mice exhibited an ameliorated response to myocardial infarction with a 33 percent reduction in infarct size without changes in systemic hemodynamics or differences in baseline ventricular morphology and function. Taken together, these findings are in agreement with previous observations of the cardioprotective role by NO in the myocardial microcirculation using exogenous NO donors and the exacerbated injury when animals were treated with NOS inhibitor.

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