Several biological activities are described to be related to eicosanoids and especially to prostanoids (prostaglandins and thromboxane). Prostanoids, as local mediators, are implicated in several functions such as renal function, platelet aggregation, neurotransmitter release, immunity modulation, smooth muscle reactivity and inflammation (Reiss et all., 2006; Norel, 2007; Matsuoka et all., 2008). They are also implicated in cancer and cardiovascular diseases such as arterial hypertension, atherosclerosis and aneurysm. For this reason, the cyclooxygenase, responsible for prostanoid synthesis, are the target of most anti-inflammatory drugs such as aspirin.
The inhibition of cyclooxygenase-2 activity by “Coxib” drugs is associated with adverse cardiovascular events in patients with inflammatory diseases. This suggests the importance of the cyclooxygenase pathway in the vascular system. The main accepted hypothesis describes an imbalance between prostacyclin and thromboxane towards a vasoconstrictor and a thrombotic effect (Grosser et all., 2006). Very few studies have explored the basic mechanisms of action associated with the intake of cyclooxygenase-2 inhibitors.
Arterial hypertension, one of these cardiovascular risks, is dependent on the muscle tone of the arterial wall. Some cyclooxygenase metabolites involved in the inflammatory response, could have a direct effect on the control of the vascular tone. Studies of physiological and biochemical pharmacology may distinguish the different roles of cyclooxygenase in the vascular wall. Actually, the different isoforms and their functions are unknown in human blood vessels. No correlation has been observed between cyclooxygenase isoforms expression, prostanoid receptor and changes in the control of vascular tone.
Figure 1: Selective inhibition of cyclooxygenase (COX)-2 and cardiovascular risks. PG: Prostaglandine, Tx: Thromboxane.
The main goal of this thesis is to clarify the role of cyclooxygenase pathway in the control tonus of human vessels under normal and inflammatory conditions. For this purpose, we have induced cyclooxygenase-2 expression in vitro in human mammary arteries and in vivo in rabbit aorta. Cyclooxygenase-2 induction causes a reduction in the vasoconstriction induced by norepinephrine. This effect is accompanied by an increase in the release of prostaglandins E2 and I2. Selective cyclooxygenase-2 inhibitors decrease the synthesis of these prostaglandins, restore and potentiate vascular tone induced by norepinephrine.
In normal conditions, prostaglandin E2 mediates different vasoactive effects. We have demonstrated pharmacologically that prostaglandin E2 induces contraction in mammary arteries via the EP3 receptor and relaxation in human pulmonary and saphenous veins via EP4 receptor activation. In these vessels, as in most other human vessels, IP receptor stimulation by prostaglandin I2 produces relaxations. Under inflammatory conditions, the relaxation of mammary artery induced by an analogue of prostaglandin I2 is reduced while that induced by the activation of the other prostanoids receptors was not altered. In addition, this effect is compensated by the high production of prostaglandin I2, since the IP antagonist restores the norepinephrine reactivity as observed with the Coxib.
Références :
- Grosser T, Fries S, FitzGerald GA. Biological basis for the cardiovascular consequences of COX-2 inhibition: therapeutic challenges and opportunities. J Clin Invest. 2006 Jan;116(1):4-15.
- Matsuoka T, Narumiya S. The roles of prostanoids in infection and sickness behaviors. J Infect Chemother. 2008 Aug;14(4):270-8.
- Norel X. Prostanoid receptors in the human vascular wall. ScientificWorldJournal. 2007 Sep 1;7:1359-74.
- Reiss AB, Edelman SD. Recent insights into the role of prostanoids in atherosclerotic vascular disease. Curr Vasc Pharmacol. 2006 Oct;4(4):395-408.
Figure 2: Vascular tone changes during Coxib treatment
Accepted articles related to this thesis:
- Foudi N, Norel X, Rienzo M, Louedec L, Brink C, Michel JB, Bäck M. Altered reactivity to norepinephrine through COX-2 induction by vascular injury in hypercholesterolemic rabbits. Am J Physiol Heart Circ Physiol. 2009 Nov;297(5):H1882-8.
- Foudi N, Louedec L, Cachina T, Brink C, Norel X. Selective cyclooxygenase-2 inhibition directly increases human vascular reactivity to norepinephrine during acute inflammation. Cardiovasc Res. 2009 Feb 1;81(2):269-77.
- Foudi N, Kotelevets L, Louedec L, Leséche G, Henin D, Chastre E, Norel X. Vasorelaxation induced by prostaglandin E2 in human pulmonary vein: role of the EP4 receptor subtype. Br J Pharmacol. 2008 Aug;154(8):1631-9.
- Kotelevets L, Foudi N, Louedec L, Couvelard A, Chastre E, Norel X. A new mRNA splice variant coding for the human EP3-I receptor isoform. Prostaglandins Leukot Essent Fatty Acids. 2007 Oct-Nov;77(3-4):195-201.