Constrictor prostanoids and uridine adenosine tetraphosphate: vascular mediators and therapeutic targets in hypertension and diabetes

Abstract

Vascular dysfunction plays a pivotal role in the development of systemic complications associated with arterial hypertension and diabetes. The endothelium, or more specifically, various factors derived from endothelial cells tightly regulate vascular function, including vascular tone. In physiological conditions, there is a balance between endothelium-derived factors, that is, relaxing factors (endothelium-derived relaxing factors; EDRFs) and contracting factors (endothelium-derived contracting factors; EDCFs), which mediate vascular homeostasis. However, in disease states, such as diabetes and arterial hypertension, there is an imbalance between EDRF and EDCF, with a reduction of EDRF signalling and an increase of EDCF signalling. Among EDCFs, COX-derived vasoconstrictor prostanoids play an important role in the development of vascular dysfunction associated with hypertension and diabetes. Moreover, uridine adenosine tetraphosphate (Up4A), identified as an EDCF in 2005, also modulates vascular function. However, the role of Up4A in hypertension-and diabetes-associated vascular dysfunction is unclear. In the present review, we focused on experimental and clinical evidence that implicate these two EDCFs (vasoconstrictor prostanoids and Up4A) in vascular dysfunction associated with hypertension and diabetes. Abbreviations AA, arachidonic acid; AICAR, 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside; AMPK, AMP-activated protein kinase; CDK2, cyclin-dependent kinase 2; cPLA2, cytosolic PLA2; DOCA, deoxycorticosterone-acetate; E2, 17β-oestradiol; ECs, endothelial cells; EDCF, endothelium-derived contracting factor; EDHF, endothelium-derived hyperpolarizing factor; EDRF, endothelium-derived relaxing factor; EPA, eicosapentaenoic acid; ER, endoplasmic reticulum; ET-1, endothelin-1; GK, Goto-Kakizaki; GPER, G protein-coupled oestrogen receptor; HETEs, hydroxyeicosatetraenoic acid; HO-1, haem oxygenase-1; HUVEC, human umbilical vein endothelial cells; L-NAME, N G -nitro-l-arginine methyl ester; L-PGDS, lipocalin-type PGD synthase; MLC20, myosin light chain 20; NO, nitric oxide; NSAIDs, non-steroidal anti-inflammatory drugs; OLETF, Otsuka Long-Evans Tokushima Fatty; OPN, osteopontin; PDGFR, platelet-derived growth factor receptor; PGI2, prostacyclin; PGIS, prostacyclin synthase; ROCK, Rho kinase; ROS, reactive oxygen species; S6K, S6 kinase; SHR, spontaneously hypertensive rats; SMCs, smooth muscle cells; STZ, streptozotocin; TP, TxA2/endoperoxide receptor; TxA2, thromboxane A2; TxS, thromboxane synthase; Up4A, uridine adenosine tetraphosphate; VP, vasopressin; WKY, Wistar-Kyoto ratsThe endothelium plays a pivotal role in the regulation of vascular tone (Vapaatalo and Mervaala, 2001;Pries and Kuebler, 2006;Flammer and Luscher, 2010;Toda et al., 2010;Flammer et al., 2012; Favero et al., 2014). In response to mechanical forces (e.g. shear stress) and endogenous ligands, endothelial cells (ECs) release a diversity of factors that mediate or directly induce vascular smooth muscle contraction or relaxation (Vapaatalo and Me...

Maternal Vascular Physiology in Preeclampsia

“…48 The TxA 2 metabolite TxB 2 is increased in the circulation and urine from women with preeclampsia, implicating TxA 2 in the pathophysiology of this disorder. 49 In omental arteries from women with preeclampsia, reduced DNA methylation of the promoter of the thromboxane synthase gene (TBXAS1) was correlated with increased expression of thromboxane synthase.…”

“…48 In isolated mesenteric arteries from pregnant rats, contractile responses to a TxA 2 mimetic (U46619) are mediated by second messengers-Rho kinase, PKC (protein kinase C), and MAPKs (mitogen-activated protein kinases)-and are inhibited by NO. 52,53 Using pregnant rats, we recently showed that release of TxB 2 (TxA 2 -stable metabolite) from mesenteric arteries was increased in rats with gestational hypertension induced by exposure to an immunogenic stimulus.…”

Mechanisms Underlying Enhanced Noradrenaline-Induced Femoral Arterial Contractions of Spontaneously Hypertensive Rats: Involvement of Endothelium-Derived Factors and Cyclooxygenase-Derived Prostanoids

“…By contrast, contractions induced by beraprost (a stable PGI 2 analogue), PGE 2 , and U46619 (thromboxane/prostanoid receptor agonist) were similar between the SHR and WKY groups. Thus, NAdinduced femoral arterial contractions are augmented in SHR resulting from endothelial dysfunction and increased COX-derived vasoconstrictor prostanoid levels.Key words cyclooxygenase; endothelium; femoral artery; hypertension; contraction Hypertension is one of the most common chronic diseases in humans, 1) and hypertension-associated vascular complications such as stroke, heart failure, kidney diseases and peripheral arterial diseases are major sources of morbidity and mortality that exacerbate the quality of life.1-3) Because dysfunction and abnormal signaling in the main structural elements of the vasculature, such as endothelial cells and smooth muscle cells, are characteristic hypertension-associated vascular complications, [4][5][6][7][8][9] and functional impairments in these cells are observed in hypertensive patients and animal models of the disease, 10-19) a comprehensive understanding of the underlying mechanisms is indispensable for preventing and treating such complications.Among endothelium-derived factors, nitric oxide (NO) is of the greatest importance for modulating vascular function. 20,21) However, other factors including endothelium-derived hyperpolarizing factor (EDHF) and cyclooxygenase (COX)-derived prostanoids can also modulate vascular tone.…”

“…[22][23][24][25] Indeed, there are several reports suggesting that contraction induced by various substances including alpha-adrenoceptor ligands is enhanced by the inhibition of EDHF signaling 26) and enhanced 27) or suppressed 11,28,29) by COX signaling in various arteries under a (patho) physiological state. Because prostacyclin (PGI 2 ) serves as an endothelium-derived vasodilator and vasoconstrictor depending on the vessel type, species, or disease condition, 4,9,30) the exact role of COX-derived prostanoids to regulate vascular tone is complicated in cardiovascular diseases including hypertension.Despite the imbalance between endothelium-derived relaxing and contracting factors in the vasculature in patients with hypertension, their exact effects on endogenous vasoconstrictor-induced contraction in femoral arteries remain unknown. In the present study, therefore, we hypothesized that femoral arteries exhibit enhanced responsiveness to noradrenaline (NAd) in the presence of hypertension due to alterations of the modulative effect of the endothelium.…”

“…[1][2][3] Because dysfunction and abnormal signaling in the main structural elements of the vasculature, such as endothelial cells and smooth muscle cells, are characteristic hypertension-associated vascular complications, [4][5][6][7][8][9] and functional impairments in these cells are observed in hypertensive patients and animal models of the disease, [10][11][12][13][14][15][16][17][18][19] a comprehensive understanding of the underlying mechanisms is indispensable for preventing and treating such complications.…”