Nitric Oxide: What a Vascular Surgeon Needs to Know

Daniel A. Popowich; Vinit Varu; Melina R. Kibbe

Disclosures

Vascular. 2007;15(6):324-335. 

In This Article

Abstract and Introduction

Abstract

Atherosclerosis in the form of peripheral arterial disease results in significant morbidity and mortality. Surgical treatment options for peripheral arterial disease include angioplasty with and without stenting, endarterectomy, and bypass grafting. Unfortunately, all of these procedures injure the vascular endothelium, which impairs its ability to produce nitric oxide (NO) and ultimately leads to neointimal hyperplasia and restenosis. To improve on current patency rates after vascular procedures, investigators are engaged in research to improve the bioavailability of NO at the site of vascular injury in an attempt to reduce the risk of thrombosis and restenosis after successful revascularization. This article reviews some of the previous research that has aimed to improve NO bioavailability after vascular procedures whether through systemic or local delivery, as well as to describe some of the NO-releasing products that are currently undergoing study for use in clinical practice.

Introduction

Atherosclerosis in the form of peripheral arterial disease (PAD) affects approximately eight million Americans, which includes 12 to 20% of individuals over the age of 65.[1] Approximately 20% of patients with PAD have typical symptoms of lower extremity claudication, rest pain, ulceration, or gangrene, and one-third have atypical exertional symptoms.[2] Persons with PAD have impaired function and quality of life even if they do not report symptoms and experience a decline in lower extremity function over time. Cardiovascular disease is the major cause of death in patients with intermittent claudication; the annual rate of cardiovascular events (myocardial infarction, stroke, or death from cardiovascular causes) is 5 to 7%.[3] Thus, PAD represents a significant source of morbidity and mortality.

Several options exist for treating atherosclerotic lesions, including percutaneous transluminal angioplasty with and without stenting, endarterectomy, and bypass grafting. Unfortunately, patency rates for each of these procedures continue to be suboptimal secondary to the development of neointimal hyperplasia. A universal feature of all vascular surgical procedures is the removal of or damage to the endothelial cell monolayer that occurs whether the procedure performed is endovascular or open. This endothelial damage leads to a decreased or absent production of nitric oxide (NO) at the site of injury (Figure 1).

Figure 1.

Schematic of neointimal hyperplasia. After vascular interventions, such as balloon angioplasty, the endothelial cell monolayer is removed and/or damaged. This leads to platelet adhesion and activation, which is followed by leukocyte chemotaxis. Vascular smooth muscle cells begin to proliferate and migrate from the media to the intima, forming the neointima, which leads to restenosis. PLT = platelet; VSMC = vascular smooth muscle cell; WBC = white blood cell.

In 1980, Furchgott and Zawadski discovered that intact endothelial cells produced a substance in response to acetylcholine stimulation.[4] This substance, termed endothelium-derived relaxing factor (EDRF), was produced only when endothelial cells were present and acted on vascular smooth muscle cells (VSMCs) to produce relaxation. Several years later, simultaneous work by two different scientists proved that EDRF is NO.[5,6] The relationship between NO and the cardiovascular system has proven to be a landmark discovery, and the scientists credited for its discovery were awarded the Nobel Prize in Medicine in 1998. Since its discovery, NO has proven to be one of the most important molecules in vascular homeostasis. In fact, the term endothelial dysfunction has now become synonymous with the reduced biologic activity of NO.[7]

NO produced by endothelial cells has been shown to have many beneficial effects on the vasculature. As described above, NO stimulates VSMC relaxation, which leads to vessel vasodilatation.[8] NO has opposite beneficial affects on endothelial cells compared with VSMCs. Whereas NO stimulates endothelial cell proliferation[9] and prevents endothelial cell apoptosis,[10] it inhibits VSMC growth and migration[11,12] and stimulates VSMC apoptosis.[13] NO also has many thromboresistant properties, such as inhibition of platelet aggregation, adhesion, and activation;[14] inhibition of leukocyte adhesion and migration;[15] and inhibition of matrix formation (Figure 2).[16] Because these properties are governed by NO, the endothelial cell monolayer is one of the most thromboresistant substances known.[17] As stated before, the endothelial cell monolayer is often removed or damaged during the time of vascular procedures, which leads to a local decrease in the production of NO. It is now understood that this loss of local NO synthesis by endothelial cells at the site of vascular injury is one of the inciting events that allows platelet aggregation, inflammatory cell infiltration, and VSMC proliferation and migration to occur in excess, which, taken together, leads to neointimal hyperplasia.

Figure 2.

Beneficial properties of nitric oxide (NO) in the vasculature. EC = endothelial cell; PLT = platelet; VSMC = vascular smooth muscle cell; WBC = white blood cell.

Reendothelialization of the injured artery can restore proper function to the artery and potentially halt the restenotic process.[18] Many studies have attempted to improve the patency of bypass grafts and stents by coating them with endothelial cells in the hope that this would restore the thromboresistant nature of native blood vessels.[19,20,21] Unfortunately, although it has been possible to coat these devices with endothelial cells, these cells do not behave like normal endothelial cells and their NO production is often diminished or absent. Because the vasoprotective properties of endothelial cells are largely carried out by NO alone, investigators are engaged in research to improve the bioavailability of NO at the site of vascular injury in an attempt to reduce the risk of thrombosis and restenosis after successful revascularization. The overall goal of using a NO-based approach is to reproduce the same thromboresistive moiety observed with normal NO production.

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