Kinins and Endothelial Control of Vascular Smooth Muscle

Jv, Mombouli; Pm, Vanhoutte

doi:10.1146/annurev.pa.35.040195.003335

Cited by 192 publications

(62 citation statements)

References 46 publications

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“…In a model of sepsis (LPS injection), the initial hypotensive response was severely curtailed in mice lacking the B1 receptor. Kinins have been suggested to be mediators of the vasodilatation observed in septic shock (25)(26)(27), and our results indicate that the B1 receptor is involved in the pathophysiological mechanism. The profound vasodilatation seen after LPS may be elicited by nitric oxide (NO), due to B1 receptors in the vasculature releasing NO via calcium-mediated activation of the endothelial NO synthase (27)(28)(29).…”

Section: Discussionsupporting

confidence: 59%

“…Kinins have been suggested to be mediators of the vasodilatation observed in septic shock (25)(26)(27), and our results indicate that the B1 receptor is involved in the pathophysiological mechanism. The profound vasodilatation seen after LPS may be elicited by nitric oxide (NO), due to B1 receptors in the vasculature releasing NO via calcium-mediated activation of the endothelial NO synthase (27)(28)(29). Because it has been shown that endothelial cells release NO immediately after administration of LPS (30), endothelial NO synthase activated by kinins via the B1 receptor may cause the early hypotensive response to LPS in intact animals.…”

Section: Discussionsupporting

confidence: 59%

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Hypoalgesia and altered inflammatory responses in mice lacking kinin B1 receptors

Pesquero

Araújo

Heppenstall

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

344

259

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Kinins are important mediators in cardiovascular homeostasis, inflammation, and nociception. Two kinin receptors have been described, B1 and B2. The B2 receptor is constitutively expressed, and its targeted disruption leads to salt-sensitive hypertension and altered nociception. The B1 receptor is a heptahelical receptor distinct from the B2 receptor in that it is highly inducible by inflammatory mediators such as bacterial lipopolysaccharide and interleukins. To clarify its physiological function, we have generated mice with a targeted deletion of the gene for the B1 receptor. B1 receptor-deficient animals are healthy, fertile, and normotensive. In these mice, bacterial lipopolysaccharide-induced hypotension is blunted, and there is a reduced accumulation of polymorphonuclear leukocytes in inflamed tissue. Moreover, under normal noninflamed conditions, they are analgesic in behavioral tests of chemical and thermal nociception. Using whole-cell patch-clamp recordings, we show that the B1 receptor was not necessary for regulating the noxious heat sensitivity of isolated nociceptors. However, by using an in vitro preparation, we could show that functional B1 receptors are present in the spinal cord, and their activation can facilitate a nociceptive reflex. Furthermore, in B1 receptor-deficient mice, we observed a reduction in the activitydependent facilitation (wind-up) of a nociceptive spinal reflex. Thus, the kinin B1 receptor plays an essential physiological role in the initiation of inflammatory responses and the modulation of spinal cord plasticity that underlies the central component of pain. The B1 receptor therefore represents a useful pharmacological target especially for the treatment of inflammatory disorders and pain.D iseases of the cardiovascular system as well as inflammatory diseases that often lead to pain are of increasing importance for health care in aging populations. Kinins have been known for some time to be important mediators of cardiovascular homeostasis, inflammation, and nociception (1). They are probably the first mediators released in injured tissue from kininogens either by plasma kallikrein, which is activated early in the coagulation cascade, or tissue kallikrein, which is activated by proteases released at injured sites. Surprisingly, the therapeutic value of intervention in the kallikrein-kinin system has not been fully explored. The two known receptors for kinins, B1 and B2, might be suitable pharmacological targets to treat chronic inflammatory and cardiovascular diseases. The B2 receptor binds the major effector peptide of the kallikrein-kinin system, which is bradykinin (BK) in rodents and kallidin in humans. Deletion of the B2 receptor in mice leads to salt-sensitive hypertension and altered nociception (2-4). Like the B2 receptor, the B1 receptor is a heptahelical receptor, but unlike B2 receptors, it is not widely expressed in normal tissue but is highly inducible by inflammatory mediators like bacterial lipopolysaccharide (LPS) and cytokines and does not desensitize after...

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Section: Discussionsupporting

confidence: 59%

Section: Discussionsupporting

confidence: 59%

Hypoalgesia and altered inflammatory responses in mice lacking kinin B1 receptors

Pesquero

Araújo

Heppenstall

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

344

259

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“…We explored next the differential regulation of S1P-mediated responses by comparing directly the signaling pathways elicited by S1P with those activated by bradykinin, a well known activator of eNOS in BAEC (39). As shown in Fig.…”

Section: Resultsmentioning

confidence: 99%

Sphingosine 1-Phosphate and Activation of Endothelial Nitric-oxide Synthase

Igarashi

Bernier

Michel

2001

Journal of Biological Chemistry

233

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Sphingosine 1-phosphate (S1P) is a platelet-derived sphingolipid that elicits numerous biological responses in endothelial cells mediated by a family of G proteincoupled EDG receptors. Stimulation of EDG receptors by S1P has been shown to activate the endothelial isoform of nitric-oxide synthase (eNOS) in heterologous expression systems (Igarashi, J., and Michel, T. (2000) J. Biol. Chem. 275, 32363-32370). However, the signaling pathways that modulate eNOS regulation by S1P/EDG in vascular endothelial cells remain less well understood. We now report that S1P treatment of bovine aortic endothelial cells (BAEC) acutely increases eNOS enzyme activity; the EC 50 for S1P activation of eNOS is ϳ10 nM. The magnitude of eNOS activation by S1P in BAEC is equivalent to that elicited by the agonist bradykinin. S1P treatment activates Akt, a protein kinase implicated in phosphorylation of eNOS. S1P treatment of BAEC leads to eNOS phosphorylation at Ser 1179 , a residue phosphorylated by Akt; an eNOS mutant in which this Akt phosphorylation site is inactivated shows attenuated S1P-induced eNOS activation. S1P-induced activation both of Akt and of eNOS is inhibited by pertussis toxin, by the phosphoinositide 3-kinase inhibitor wortmannin, and by the intracellular calcium chelator BAPTA (1,2-bis(aminophenoxy)ethane-N,N,N,N-tetraacetic acid). By contrast to S1P, activation of G protein-coupled bradykinin B2 receptors neither activates kinase Akt nor promotes Ser 1179 eNOS phosphorylation despite robustly activating eNOS enzyme activity. Understanding the differential regulation of protein kinase pathways by S1P and bradykinin may lead to the identification of new points for eNOS regulation in vascular endothelial cells.

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“…These include acetylcholine (produced by endothelial cells; see Physical Signals section of this article), adiponectin (produced by perivascular adipose tissues; see Other Hormones and Circulating Mediators section of this article), angiotensin [1][2][3][4][5][6][7] (formed from angiotensin II by angiotensin-converting enzyme 2), bradykinin (produced by vascular kallikrein), endothelin-1, histamine (produced by mast cells), prostacyclin (produced by endothelial cells), prostaglandin E 2 (produced presumably by endothelial cells), and vascular endothelial growth factor (produced in response to hypoxia). 5,14,15,80 …”

Section: Vascular Signalsmentioning

confidence: 99%

Thirty Years of Saying NO

Vanhoutte

Zhao

et al. 2016

Circulation Research

331

156

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T he historical demonstration by Furchgott and Zawadzki 1 that removal of the endothelium abrogates the in vitro vasodilator effect of acetylcholine has led to the identification 30 years ago of nitric oxide (NO) as a major endogenous local regulator of vascular tone. [2][3][4][5][6][7][8][9][10] When the ability of endothelial cells to produce NO is blunted, the ensuing vascular dysfunction sets the stage for the occurrence of cardiovascular disease in general, and atherosclerosis in particular. [11][12][13][14][15] This review focuses, stepby-step, on the bioavailability (production, action, and disposition) of endothelium-derived NO as local regulator of vascular tone in health and disease. Obviously, there is much more than NO in the control of the degree of contraction of underlying vascular smooth muscle cells exerted by the endothelial cells. Indeed, they generate also prostacyclin and hyperpolarizing signals (initiating endothelium-dependent hyperpolarization [EDH] and thus relaxation) and produce vasoconstrictor mediators (endothelium-derived contracting factors and the peptide endothelin-1); those have been discussed elsewhere in detail. 15-22 Endothelial Sources of NO NO SynthaseThree NO synthase (NOS) isozymes, which are encoded by different genes, catalyze the production of NO from l-arginine: neuronal NOS (or NOS-1), cytokine-inducible NOS (iNOS or NOS-2), and endothelial NOS (eNOS or NOS-3).6,23-25 Although iNOS can be induced (by lipopolysaccharides and inflammatory cytokines) and neuronal NOS can be present in the blood vessel

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Kinins and Endothelial Control of Vascular Smooth Muscle

Cited by 192 publications

References 46 publications

Hypoalgesia and altered inflammatory responses in mice lacking kinin B1 receptors

Hypoalgesia and altered inflammatory responses in mice lacking kinin B1 receptors

Sphingosine 1-Phosphate and Activation of Endothelial Nitric-oxide Synthase

Thirty Years of Saying NO

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