Endothelin-1 and platelet activating factor stimulate thromboxane A2 biosynthesis in rat vascular smooth muscle cells

Takayasu-Okishio, M.; Terashita, Zen‐ichi; Kondo, Koichi

doi:10.1016/0006-2952(90)90592-9

Cited by 46 publications

(3 citation statements)

References 17 publications

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“…Further, TP-receptors are coupled to G α12/13 , hence their stimulation should activate Rho [ 85 ], unless TP-receptors are primarily coupled to G αq/11 [ 80 ]. Notably, vasoconstrictors such as endothelin-1 or platelet-activating factor also mediate their contractile effect via the release of TXA 2 [ 86 , 87 ].…”

Section: Discussionmentioning

confidence: 99%

PDGF-BB regulates the pulmonary vascular tone: impact of prostaglandins, calcium, MAPK- and PI3K/AKT/mTOR signalling and actin polymerisation in pulmonary veins of guinea pigs

et al. 2018

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BackgroundPlatelet-derived growth factor (PDGF)-BB and its receptor PDGFR are highly expressed in pulmonary hypertension (PH) and mediate proliferation. Recently, we showed that PDGF-BB contracts pulmonary veins (PVs) and that this contraction is prevented by inhibition of PDGFR-β (imatinib/SU6668). Here, we studied PDGF-BB-induced contraction and downstream-signalling in isolated perfused lungs (IPL) and precision-cut lung slices (PCLS) of guinea pigs (GPs).MethodsIn IPLs, PDGF-BB was perfused after or without pre-treatment with imatinib (perfused/nebulised), the effects on the pulmonary arterial pressure (PPA), the left atrial pressure (PLA) and the capillary pressure (Pcap) were studied and the precapillary (Rpre) and postcapillary resistance (Rpost) were calculated. Perfusate samples were analysed (ELISA) to detect the PDGF-BB-induced release of prostaglandin metabolites (TXA2/PGI2). In PCLS, the contractile effect of PDGF-BB was evaluated in pulmonary arteries (PAs) and PVs. In PVs, PDGF-BB-induced contraction was studied after inhibition of PDGFR-α/β, L-Type Ca2+-channels, ROCK/PKC, prostaglandin receptors, MAP2K, p38-MAPK, PI3K-α/γ, AKT/PKB, actin polymerisation, adenyl cyclase and NO. Changes of the vascular tone were measured by videomicroscopy. In PVs, intracellular cAMP was measured by ELISA.ResultsIn IPLs, PDGF-BB increased PPA, Pcap and Rpost. In contrast, PDGF-BB had no effect if lungs were pre-treated with imatinib (perfused/nebulised). In PCLS, PDGF-BB significantly contracted PVs/PAs which was blocked by the PDGFR-β antagonist SU6668. In PVs, inhibition of actin polymerisation and inhibition of L-Type Ca2+-channels reduced PDGF-BB-induced contraction, whereas inhibition of ROCK/PKC had no effect. Blocking of EP1/3- and TP-receptors or inhibition of MAP2K-, p38-MAPK-, PI3K-α/γ- and AKT/PKB-signalling prevented PDGF-BB-induced contraction, whereas inhibition of EP4 only slightly reduced it. Accordingly, PDGF-BB increased TXA2 in the perfusate, whereas PGI2 was increased in all groups after 120 min and inhibition of IP-receptors did not enhance PDGF-BB-induced contraction. Moreover, PDGF-BB increased cAMP in PVs and inhibition of adenyl cyclase enhanced PDGF-BB-induced contraction, whereas inhibition of NO-formation only slightly increased it.ConclusionsPDGF-BB/PDGFR regulates the pulmonary vascular tone by the generation of prostaglandins, the increase of calcium, the activation of MAPK- or PI3K/AKT/mTOR signalling and actin remodelling. More insights in PDGF-BB downstream-signalling may contribute to develop new therapeutics for PH.

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Section: Discussionmentioning

confidence: 99%

PDGF-BB regulates the pulmonary vascular tone: impact of prostaglandins, calcium, MAPK- and PI3K/AKT/mTOR signalling and actin polymerisation in pulmonary veins of guinea pigs

et al. 2018

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“…EDCF is generated by ET-1 which stimulates thromboxane A 2 (T × A 2 ) biosynthesis [46] whereas activation of TP-Rs releases ET-1 [47] and generates ROS [48,49]. In turn, ROS are required for microvascular EDCF responses mediated by TP-R [30,50], can enhance responses to TP and ET receptor stimulation [15] and can stabilize TP-Rs in active form [51].…”

Section: Discussionmentioning

confidence: 99%

Microvascular Endothelial Dysfunction and Enhanced Thromboxane and Endothelial Contractility in Patients with HIV

et al. 2013

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1.1. Background The prevalence of cardiovascular disease is increased with human immunodeficiency virus (HIV) infection, but the mechanism is unclear. We hypothesized that HIV increases microvascular reactive oxygen species, thereby impairing endothelial function and enhancing contractility. 1.2. Method Subcutaneous microarterioles were isolated from gluteal skin biopsies in premenopausal, African American, HIV positive women receiving effective anti-retroviral therapy, but without cardiovascular risk factors except for increased body mass index (n=10) and healthy matched controls (n=10). The arterioles were mounted on myographs, preconstricted and relaxed with acetylcholine for: endothelium-dependent relaxation, endothelium-dependent relaxation factor (nitric oxide synthase-dependent relaxation), endothelium-dependent hyperpolarizing factor (potassium-channel dependent relaxation) and endothelium-independent relaxation (nitroprusside). Contractions were tested to endothelium-dependent contracting factor (acetylcholine contraction with blocked relaxation); phenylephrine, U-46,619 and endothelin-1. Plasma L-arginine and asymmetric dimethylarginine were measured by high performance capillary electrophoresis. 1.3. Results The micro-arterioles from HIV positive women had significantly (% change in tension; P<0.05) reduced acetylcholine relaxation (-51 ± 6 vs. -78 ± 3%), endothelium-dependent relaxation factor (-28 ± 4 vs. -39 ± 3%), endothelium-dependent hyperpolarizing factor (-17 ± 4 vs. -37 ± 4%) and decreased nitric oxide activity (0.16 ± 0.03 vs. 0.70 ± 0.16 Δ unit) but unchanged nitroprusside relaxation. They had significantly enhanced endothelium-dependent contracting factor (+21 ± 6 vs. +7 ± 2%) and contractions to U-46,619 (+164 ± 10 vs. +117 ± 11%) and endothelin-1(+151 ± 12 vs. +97 ± 9%), but not to phenylephrine. There was enhanced reactive oxygen species with acetylcholine (0.11 ± 0.02 vs. 0.05 ± 0.01 Δ unit; P<0.05) and endothelin-1 (0.31 ± 0.06 vs. 0.10 ± 0.02 Δ unit; P<0.05). Plasma L-arginine: assymetric dimethyl arginine rates was reduced (173 ± 12 vs. 231 ± 6 μmol·μmol-1, P<0.05). 1.4. Conclusion Premenopausal HIV positive womenhad microvascular oxidative stress with severe endothelial dysfunction and reduced nitric oxide and arginine: assymetric dimethylarginine ratio but enhanced endothelial, thromboxane and endothelin contractions. These microvascular changes may herald later cardiovascular disease.

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“…Moreover, the rise in BP induced by VEGF inhibition can be fully reversed in animals by ET-1 receptor blockade with either a selective ET A antagonist (ABT-627) as well as with a dual ET A and ET B antagonist (ACT-064992) [14], [15]. However, additional contractile mechanisms, predominantly elevated prostanoid signaling, may exacerbate the ET-1-induced BP elevation during VEGF inhibition as ET-1 stimulates production of the vasocontractile prostanoid thromboxane A 2 (TXA 2 ) [16], [17]. Production of TXA 2 is indeed elevated in pre-eclampsia and results in a decreased prostacyclin/TXA 2 ratio [18], [19].…”

Section: Introductionmentioning

confidence: 99%

SFlt-1 Elevates Blood Pressure by Augmenting Endothelin-1-Mediated Vasoconstriction in Mice

et al. 2014

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ObjectiveScavenging of vascular endothelial growth factor (VEGF) elevates blood pressure (BP) in patients receiving anti-angiogenic therapy. Similarly, inhibition of circulation VEGF by its soluble receptor fms-like tyrosine kinase-1 (sFlt-1) underlies BP elevation in pre-eclampsia. Both phenotypes are characterized by augmented production of endothelin-1 (ET-1), suggesting a role for ET-1 in anti-angiogenic hypertension. We aimed to assess the effect of VEGF inhibition on ET-1-induced contractility and downstream ET-1 signaling.Approach and ResultsMale C57BL/6N mice were treated with either sFlt-1 or vehicle and BP was assessed via tail-cuff. Mean arterial pressure of sFlt-1-treated mice markedly increased compared to vehicle-treated controls (N = 11–12, p<0.05). After sacrifice, carotid and mesenteric arteries were isolated for isometric tension measurements. ET-1-induced contractions were similar in mesenteric arteries of vehicle and sFlt-1-treated mice, but augmented in carotid segments of sFlt-1-treated mice compared to controls (N = 9–10, p<0.05). The increased contraction in carotid segments could be completely abrogated by the cyclooxygenase (COX) inhibitor indomethacin (N = 9–10, p<0.05), indicating heightened prostaglandin-mediated vasoconstriction. This was associated with a shift towards procontractile ETB signaling in sFlt-1-treated mice, possibly explaining the increased ET-1-induced prostaglandin-mediated vasoconstriction. In line with the ex vivo findings, sFlt-1-induced BP elevation could be prevented in vivo by oral treatment with either a high-dose of the COX inhibitor aspirin (N = 7) or with picotamide (N = 9), a dual thromboxane A2 synthase inhibitor and receptor antagonist.ConclusionsVEGF inhibition augments the pressor response to ET-1. The cyclooxygenase-thromboxane signaling route downstream of ET-1 might be a possible target to prevent BP elevation during VEGF inhibition.

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Endothelin-1 and platelet activating factor stimulate thromboxane A2 biosynthesis in rat vascular smooth muscle cells

Cited by 46 publications

References 17 publications

PDGF-BB regulates the pulmonary vascular tone: impact of prostaglandins, calcium, MAPK- and PI3K/AKT/mTOR signalling and actin polymerisation in pulmonary veins of guinea pigs

PDGF-BB regulates the pulmonary vascular tone: impact of prostaglandins, calcium, MAPK- and PI3K/AKT/mTOR signalling and actin polymerisation in pulmonary veins of guinea pigs

Microvascular Endothelial Dysfunction and Enhanced Thromboxane and Endothelial Contractility in Patients with HIV

SFlt-1 Elevates Blood Pressure by Augmenting Endothelin-1-Mediated Vasoconstriction in Mice

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