Gene expression changes of prostanoid synthases in endothelial cells and prostanoid receptors in vascular smooth muscle cells caused by aging and hypertension

Abstract

The present study was designed to assess whether or not changes in genomic expression of cyclooxygenases (COX-1, COX-2), endothelial nitric oxide synthase (eNOS), and prostanoid synthases in the endothelium and of prostanoid receptors in vascular smooth muscle contribute to the occurrence of endothelium-dependent contractions during aging and hypertension. Gene expression was quantified by real-time PCR using isolated endothelial cells and smooth muscle cells (SMC) from the aorta of Wistar-Kyoto and spontaneously hypertensive rats. Genes for all known prostanoid synthases and receptors were present in endothelial cells and SMC, respectively. Aging caused overexpression of eNOS, COX-1, COX-2, thromboxane synthase, hematopoietic-type prostaglandin D synthase, membrane prostaglandin E synthase-2, and prostaglandin F synthase in endothelial cells and COX-1 and prostaglandin E 2 (EP)4 receptors in SMC. Hypertension augmented the expression of COX-1, prostacyclin synthase, thromboxane synthase, and hematopoietic-type prostaglandin D synthase in endothelial cells and prostaglandin D 2 (DP), EP3, and EP4 receptors in SMC. The increase in genomic expression of endothelial COX-1 explains why in aging and hypertension the endothelium has greater propensity to release cyclooxygenase-derived vasoconstrictive prostanoids. The expression of prostacyclin synthase was by far the most abundant, explaining why the majority of the COX-1-derived endoperoxides are transformed into prostacyclin, substantiating the role of prostacyclin as an endothelium-derived contracting factor. The expression of thromboxane synthase was increased in the cells of aging or hypertensive rats, explaining why the prostanoid can contribute to endothelium-dependent contractions. It is uncertain whether the gene modifications caused by aging and hypertension directly contribute to endotheliumdependent contractions or rather to vascular aging and the vascular complications of the hypertensive process. endothelium-dependent contractions; endothelium-derived contracting factors; prostacyclin synthase; prostacyclin; real-time quantitative polymerase chain reaction THE OCCURRENCE of endothelium-dependent contractions is accelerated by aging and hypertension (13,17,19,39,42). Thus such contractions are observed readily in aortas from adult spontaneously hypertensive rats (SHR) and aged normotensive Wistar-Kyoto rats (WKY) (17,19,42). The mediators of endothelium-dependent contractions are produced by endothelial cyclooxygenase (7,12,33) and have been termed endothelium-derived contracting factors (EDCFs). EDCF is unlikely to be a single substance but rather is constituted of a mixture of prostanoids, the formation of which depends on the vascular bed, the age, and the condition of the species studied. Thus prostacyclin (9, 10, 27), endoperoxides (7, 14), and thromboxane A 2 (10, 11, 29) have been proposed as EDCFs. Cyclooxygenase breaks down arachidonic acid to form endoperoxides, which are subsequently converted into prostacyclin, thromboxane A 2 , prostaglandin...

Upregulation of Heme Oxygenase 1 by Hemin Impairs Endothelium-Dependent Contractions in the Aorta of the Spontaneously Hypertensive Rat

“…This conclusion is supported by the following observations: when hemin treatment potentiated acetylcholine-induced relaxations, it did so in particular by attenuating the secondary contractile phase of the concentration-response curve, which has been attributed to the generation of EDCFs 18,29 ; and contractions of quiescent aortic rings with endothelium induced by acetylcholine and the calcium ionophore A23187 were impaired in preparations of the hemin-treated rats compared with controls. This impairment of endothelium-dependent contractions cannot be attributed to direct effects of HO products and was not reversed by acute HO inhibition.…”

α1‐Adrenoceptor activation of PKC‐ε causes heterologous desensitization of thromboxane receptors in the aorta of spontaneously hypertensive rats

“…The sympathetic nervous system is hyperactive in the SHR (Head et al, 1985;Scott and Galway, 1985;Mangiarua and Lee, 1990;Ely et al, 1997). Thus, the interaction observed in the present study between the downstream effects of α1-adrenoceptor activation and the response to PGE2 may play a modulating role in reducing prostanoidinduced vasoconstriction in the SHR, in which such responses are prominent (Lüscher and Vanhoutte, 1986;Tang et al, 2005;Tang and Vanhoutte, 2008).…”

Cyclooxygenase-2-Derived Prostaglandin F 2α

“…The expression of TP receptors remained unchanged, similar to another study from the same group in aged rats. 7 In this study on normotensive and hypertensive rats, genomic expression of endothelial COX-1 was increased, suggesting a greater potency to generate and release EDCFs in aging and hypertension. 7 A significant contribution of COX-1-derived EDCFs in the study of Wong et al 10 in hamsters is unlikely.…”

“…7 In this study on normotensive and hypertensive rats, genomic expression of endothelial COX-1 was increased, suggesting a greater potency to generate and release EDCFs in aging and hypertension. 7 A significant contribution of COX-1-derived EDCFs in the study of Wong et al 10 in hamsters is unlikely. Thus, there might be species differences not only regarding the chemical identity of EDCF(s) but also the biosynthetic pathways and site(s) of action.…”

“…1 One reason for this is the upregulation of endothelial COXs and enzymes of PG-endoperoxide catabolism during the aging process and hypertension with enhanced generation of these compounds 6,7 ; another reason is the low selectivity of prostanoids for their membrane receptors. Vasoconstrictor prostanoids act on vascular smooth muscle cells via the thromboxane-prostanoid (TP) receptor.…”