Date Published: November 1, 2011
Publisher: Hindawi Publishing Corporation
Author(s): Takayuki Matsumoto, Rita C. Tostes, R. Clinton Webb.
The endothelium plays a pivotal role in vascular homeostasis, and endothelial dysfunction is a major feature of cardiovascular diseases, such as arterial hypertension, atherosclerosis, and diabetes. Recently, uridine adenosine tetraphosphate (Up4A) has been identified as a novel and potent endothelium-derived contracting factor (EDCF). Up4A structurally contains both purine and pyrimidine moieties, which activate purinergic receptors. There is an accumulating body of evidence to show that Up4A modulates vascular function by actions on endothelial and smooth muscle cells. In this paper, we discuss the effects of Up4A on vascular function and a potential role for Up4A in cardiovascular diseases.
A healthy endothelium expresses and releases various molecules, which aid to maintain vascular structure and homeostasis [1, 2]. Endothelial cells actively regulate basal vascular tone and vascular reactivity in physiological and pathophysiological conditions, by responding to mechanical forces (e.g., shear stress) and neurohumoral mediators with the release of a variety of relaxing factors [endothelium-derived relaxing factors (EDRFs)] or contracting factors [endothelium-derived contracting factors (EDCFs)] [3–5]. Endothelial dysfunction plays a key role in the initiation and development of both macro- and microangiopathy in patients with arterial hypertension, inflammatory-associated diseases (atherosclerosis), hypercholesterolemia, stroke, diabetes, as well as in animal models of these diseases [4–12]. The mechanisms that regulate the balance between EDRFs and EDCFs are important for vascular health. Mechanisms that increase EDRFs and/or decrease the release and/or bioavailability of EDCFs are promising drug targets to alleviate the damage caused by endothelial dysfunction. So far, several factors are known as EDCFs such as endothelin-1, angiotensin II, vasoconstrictor prostanoids, and reactive oxygen species [4, 5, 13].
Several reports demonstrated that Up4A modulates vasomotor activity in vessels from nondisease animal models using both in vitro (i.e., perfusion or myograph system) and in vivo techniques (Table 1, Figure 1). Since Up4A possesses both purine and pyrimidine moiety, these studies mainly focus on the relationship between Up4A and purinoceptor signaling.
There is evidence that Up4A might have implications in the pathogenesis of human arterial hypertension. Jankowski et al.  demonstrated that the plasma concentrations of Up4A are increased in juvenile hypertensive humans compared with normotensive subjects. Up4A concentration significantly correlates with the left ventricular mass and intima/media wall thickness in the hypertensive patients . Therefore, Up4A may have an association with hypertension and hypertension-related vascular abnormalities.
The present work reviews reported studies on the effects of Up4A on vascular function in physiological and pathophysiological states. Although Up4A definitely has an important role in vascular function, some questions currently remain unresolved. For instance, what are the mechanisms of synthesis and catabolism of Up4A? To what extent are there regionally differences in Up4A kinetics? Are there mechanisms modified in vessels under physiological and pathophysiological states? How and to what extent do Up4A receptor(s) interact with Up4A putative degradation forms (e.g., mononucleotides and nucleotides) in the vascular system? How do the vascular actions of Up4A change during aging? Are there sex differences in the response to the dinucleotide? Since ion channels (e.g., P2X receptor) and G protein-coupled receptor (e.g., P2Y receptor and adenosine receptor) participate in multiprotein complexes with signaling molecules and other receptors (dimerized receptor or unknown Up4A specific receptor) should also be investigated in physiological and pathophysiological states. A comprehension of the vascular effects of Up4A in other cardiovascular diseases, such as atherosclerosis, diabetes, and stroke should also be encouraged.