The Endothelium in Health and Disease-A Target for Therapeutic Intervention.

Abstract

In this review we discuss the contribution of NO, prostacyclin and endothelium-derived relaxing factor--endothelium-derived hyperpolarizing factor, or EDHF, to vascular function. We also explore the hypotheses (1): that tissues can store NO as nitrosothiols (RSNOs) and (2) that such RSNO stores can be modulated by physiological and pathophysiological processes. Notably in the microcirculation, EDHF appears to play an important role in the regulation of vascular tone. Leading candidates for EDHF include extracellular potassium (K+), an epoxygenase product, hydrogen peroxide and/or a contribution from myoendothelial gap junctions. Data from our laboratory indicate that in mouse vessels, different endothelium-dependent vasodilators, such as acetylcholine and protease-activated receptor (PAR) agonists, release different endothelium-derived relaxing factors. The combination of two K-channel toxins, apamin and charybdotoxin, inhibits EDHF activity in most protocols. Endothelial dysfunction is considered as the major risk factor and a very early indicator of cardiovascular disease including the cardiovascular complications of type I & types II diabetes. Impaired endothelium-dependent vasodilatation results primarily from a decreased synthesis of endothelium-derived nitric oxide (NO) and/or an increase in the production of reactive oxygen species such as superoxide. We have shown that the administration of tetrahydrobiopterin, an important co-factor for nitric oxide synthase (NOS) partially restores endothelial function (1) in leptin-deficient mice (db/db) with spontaneous type II diabetes, as well as (2) in human vascular tissue harvested for coronary artery bypass grafting (CABG). These data suggest that a deficiency in the availability of tetrahydrobiopterin plays an important role in vascular dysfunction associated with Type II diabetes. In addition, changes in the contribution of EDHF occur in vascular tissue from the db/db mice suggesting a compensatory increase in EDHF production; whether this alteration in EDHF production is physiological or pathophysiological remains controversial.

Acetylcholine-induced vasodilation in the perfused kidney of the streptozotocin-induced diabetic rat: role of prostacyclin

“…Indeed, there are several pieces of evidence to suggest that such compensatory interactions occur in various pathophysiological states (Triggle et al, 2003;Bryan et al, 2005).…”

“…Although nitric oxide (NO) appears to account for the actions of ACh in many settings, elimination of NO (e.g., by hemoglobin or NO-synthase inhibitors) does not always prevent endothelium-dependent vasodilation. Thus, evidence has accrued to suggest Correspondence to: Katsuo Kamata, Ph.D., Department of Physiology and Morphology, Institute of Medicinal Chemistry, Hoshi University, Shinagawa-ku, Tokyo 142-8501, Japan Phone: that EDRFs other than NO may contribute to the vascular actions of ACh (Triggle et al, 2003;Matsumoto et al, 2004a;Tanaka et al, 2004). It is well appreciated that ACh stimulates the endothelial production of vasodilatory prostaglandins (Salom et al, 1991;Majid and Navar, 1992;Vizioli et al, 2005), and current evidence suggests that an endothelium-derived hyperpolarizing factor (EDHF) may also contribute to the vasodilator actions of ACh (Busse et al, 2002;Chen et al, 1988;Matsumoto et al, 2003aMatsumoto et al, , 2003bMatsumoto et al, , 2005Matsumoto et al, , 2006aMatsumoto et al, , 2006bTakano et al, 2005;Yamamoto and Suzuki, 2005).…”

Relationships among ET-1, PPAR.GAMMA., oxidative stress and endothelial dysfunction in diabetic animals

“…They do this by responding to mechanical forces and neurohumoral mediators with the release of a variety of contracting [endothelium-derived contracting factors (EDCFs)] and relaxing factors [endothelium-derived relaxing factors (EDRFs)] (Cohen, 2005;Kamata et al, 1989;Kobayashi et al, 2005;Matsumoto et al, 2004aMatsumoto et al, , 2006aPieper, 1998;Triggle et al, 2003;Vanhoutte et al, 2005). A balanced release of these bioactive factors facilitates vascular homeostasis.…”

“…There is an accumulating body of evidence to show that in several vessels, the endotheliumdependent relaxation responses are weaker in experimental models of cardiovascular diseases and in patients with such diseases (De Vriese et al, 2000;Kamata et al, 1989;Kobayashi et al, 2000Kobayashi et al, , 2005Poston and Taylor, 1995;Sekiguchi et al, 2004;Triggle et al, 2003). Further, improvements in such impaired relaxation responses have been reported following treatment with a PPARγ agonist.…”

“…The TZDs are currently used in the treatment of diabetic hyperglycemia (Stumvoll and Haring, 2002), although these compounds may have direct beneficial effects on cardiovascular risk that are independent of their hypoglycemic actions (Martens et al, 2002). Several lines of evidence suggest that endothelial dysfunction plays a key role in the development of both macro-and microangiopathy in patients with inflammatory-associated diseases as atherosclerosis, hypercholesterolemia, hypertension, stroke, and diabetes, as well as in animal models of these diseases (Cai and Harrison, 2000;Kobayashi et al, 2000, Landmesser et al, 2004Matsumoto et al, 2003Matsumoto et al, , 2004bMatsumoto et al, , 2005Triggle et al, 2003). Although the genesis of this endothelial dysfunction and its associated vasomotor abnormalities remains poorly understood, there have been recent demonstrations that in cardiovascular diseases, activation of PPARγ not only has cardio-protective effects, but also restores vascular structure and corrects endothelial dysfunction (Bishop-Bailey, 2000;Li and Palinski, 2006;Schiffrin, 2005;Touyz and Schiffrin, 2006;Walcher and Marx, 2004).…”