Hypercholesterolemia and Postcapillary Venules

Natural Cholesterol Guide

Lower Cholesterol Ebook

Get Instant Access

Although large veins appear to be relatively unaffected by acute or chronic elevations in blood cholesterol concentration, postcapillary venules in the diameter range of 20 to 40 mm exhibit profound changes in response in these conditions. Some of the alterations in signaling and inflammatory pathways induced in arterioles by hypercholesterolemia are also manifested in venules. For example, the reduced NO bioavailability and elevated ROS production are seen in both segments of the microvasculature. However, the consequences of these changes vary between the vascular segments, with NO and ROS exerting minimal influence on the diameter of venules while exerting a profound effect on arte-rioles. In venules, NO exerts a major influence on the expression of cellular adhesion molecules and consequently serves to minimize the adhesive interactions between circulating blood cells and venular endothelium. However, during hypercholesterolemia the expression of several adhesion molecules is increased on venular endothelium. These adhesion molecules support the leukocyte infiltration and platelet-endothelial interactions that occur in postcapillary venules when blood cholesterol concentration is elevated.

Blood Cell-Endothelial Cell Interactions

The use of blocking antibodies and mutant mice has revealed key roles for several adhesion molecules in the pathogenesis of atherosclerosis. The adhesion molecules that contribute to the binding of leukocytes and platelets in postcapillary venules during hypercholesterolemia have been less well defined. oxLDL also causes degradation of the endothelial glycocalyx in venules. It is noteworthy that this leads to loss of heparin sulfate proteoglycans, which would normally contribute to the negative charge and anti-adhesive properties of the normal endothelial cell. Hence, the increased adhesion molecule expression (and possibly the oxidatively modified surface of the endothelial cell) causes the endothelial cells to assume a phenotype that supports the adhesion of leukocytes and platelets during hypercholesterolemia.

Both intercellular adhesion molecule-1 (ICAM-1) and p-selectin are upregulated on venular endothelium when mice are placed on a cholesterol-enriched diet for 1 week. This protein expression coincides with the recruitment of leukocytes. In the early stages of leukocyte recruitment in hypercholesterolemic venules, neutrophils appear to represent the major cell population that interacts with the vessel wall. Both CD4+ and CD8+ T-lymphocytes participate in this response, but in an indirect manner, by producing cytokines that upregulate endothelial cell adhesion molecules.

platelets are also recruited into postcapillary venules during acute hypercholesterolemia. It has been demonstrated using knockout mice that the platelets interact with the venular wall via p-selectin that is expressed on the surface of circulating platelets, although p-selectin on venular endothelium also contributes but to a lesser extent. The latter may participate by binding p-selectin glycoprotein ligand-1 (PSGL-1) on leukocytes, which in turn may serve as a platform for platelet binding to the venular wall. oxLDL promotes the formation of leukocyte-platelet aggregates that can interact with the venular wall. The formation of these aggregates can be inhibited using a P-selectin blocking antibody suggesting that platelet p-selectin is interacting with PSGL-1 on the leukocytes.

Nitric Oxide and Reactive Oxygen Species

Although there are very few mechanistic data available on platelet accumulation in postcapillary venules, a large body of evidence supports a role for an NO-ROS imbalance in the hypercholesterolemia-induced leukocyte-endothelial cell interactions. First, NO inhibitors fail to exacerbate leukocyte adhesion responses in postcapillary venules of hypercholesterolemic mice, unlike the greatly enhanced responses observed in normal mice. This suggests that basal NO release is impaired, possibly because of the augmented circulating levels of ADMA mentioned earlier. Exposure of normal postcapillary venules to an analog of ADMA (at levels comparable to circulating levels during hypercholes-terolemia) elicits leukocyte adhesion in venules and impairs endothelial barrier function, supporting the proposal that the elevated ADMA levels during hypercholesterolemia are indeed proinflammatory. Second, many NO donors (e.g., sodium nitroprusside, spermine-NO, and L-arginine) have been successfully employed to reduce the inflammatory responses (adhesion molecule expression and leukocyte accumulation) observed both in diet-induced hypercholes-terolemia and following exposure to oxLDL, supporting a role for decreased NO bioavailability in this leukocyte recruitment process.

The importance of ROS in the venular responses to hypercholesterolemia is underscored by the observation that oxidative stress, measured using an oxidant-sensitive fluorescent probe, is elevated in postcapillary venules of hypercholesterolemic mice when compared with their normocholesterolemic counterparts. This coincides with increases in leukocyte adhesion and emigration in venules. Furthermore, the leukocyte recruitment is profoundly attenuated in CuZn-SOD-overexpressing mice, suggesting that O2- is a major component of the ROS generated during hypercholesterolemia. Similarly, administration of CuZn-SOD has been shown to be effective in preventing oxLDL-induced venular responses. The enzymes that contribute to the increased ROS generation in hypercholesterolemic venules have not been clearly defined. However, mice that are genetically deficient in the p47phox subunit of NAD(P)H oxidase demonstrate a significantly lower level of leukocyte recruitment in response to hypercholesterolemia. Interestingly, when bone marrow chimeras were made to separate blood cell versus vessel wall sources of this enzyme, both sources appeared to be equally important in the generation of the inflammatory phenotype observed in postcapillary venules after 2 weeks on a cholesterol-enriched diet.

Other Inflammatory Mediators

Several mediators have been implicated in inflammatory responses of venules to oxLDL- or diet-induced hypercholesterolemia. For example, arachidonic acid metabolism appears to be important in oxLDL-induced leukocyte recruitment. Blocking leukotriene biosynthesis can prevent the leukocyte adhesion elicited by oxLDL in both arterioles and venules. Platelet-activating factor (PAF) receptor antagonists are equally effective in attenuating the inflammatory responses to oxLDL. Although the contribution of these lipid mediators to diet-induced microvascular alterations has not been assessed, a role for these factors in diet-induced atherosclerotic lesion formation is well established, supporting the possibility that they may also contribute to the early inflammatory responses elicited in venules.

The T-cell-derived cytokine interferon-g (IFN-g) has also been implicated in vascular responses to hypercholes-terolemia. IFN-g can promote adhesion molecule expression, and it is a potent activator of NAD(P)H oxidase. The microvasculature of IFN-g-knockout mice exhibits reduced leukocyte adhesion and significantly lower oxidant stress in response to hypercholesterolemia, when compared with wild-type mice. This suggests that T-lymphocytes may be mediating the inflammatory responses to hypercholes-terolemia via IFN-g, and that this cytokine acts by promoting ROS generation. Another step in this inflammatory pathway may be the release of IL-12, a cytokine that is intimately linked to IFN-g production. Like IFN-g, IL-12 is expressed in atherosclerotic lesions and it has recently been shown to contribute to the oxidative stress and leukocyte recruitment induced in postcapillary venules by hypercho-lesterolemia. These observations suggest that IFN-g and IL-12 act in concert to promote leukocyte adhesion and emigration by enhancing the production of ROS.

Was this article helpful?

0 0
Lower Your Cholesterol In Just 33 Days

Lower Your Cholesterol In Just 33 Days

Discover secrets, myths, truths, lies and strategies for dealing effectively with cholesterol, now and forever! Uncover techniques, remedies and alternative for lowering your cholesterol quickly and significantly in just ONE MONTH! Find insights into the screenings, meanings and numbers involved in lowering cholesterol and the implications, consideration it has for your lifestyle and future!

Get My Free Ebook

Post a comment