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Assessing Myogenic Response and Vasoactivity In Resistance Mesenteric Arteries Using Pressure Myography
Published on: July 6, 2015
p38 mitogen-activated protein kinase activation is required for thromboxane- induced contraction in perfused and
Manlio Bolla1, Khalid Matrougui, Laurent Loufrani
1INSERM, U348, IFR Circulation-Paris-Nord, Paris VII University, Hôpital Lariboisière, Paris, France.
Abstract:
Thromboxane A(2) (TxA2) is a potent proaggregating, vasoconstrictor agent produced in many physiological and pathological situations. Although mitogen-activated protein (MAP) kinases [MAPK (ERK1/2 and p38)] have been shown to be activated after endoperoxide/thromboxane receptor (TP) stimulation, no study has investigated their potential role in resistance arteries, especially in physiological conditions of pressure and flow in which the arteries can contract. Thus, responses to TP stimulation by the stable agonist U46619 were studied in isolated rat mesenteric resistance arteries (inner diameter 262 +/- 5 microm) mounted in an arteriograph. Changes in diameter were recorded under physiological levels of flow (90 microl/min) and pressure (50 mm Hg). TP stimulation induced a concentration-dependent contraction (EC(50) value of 1.94 +/- 0.22 x 10(-7) M), without desensitization. U46619-induced contraction was inhibited by calcium entry blockade (nifedipine) and protein kinase C inhibition (GF109203X), but it was not affected by tyrosine kinase inhibition (tyrphostin A25). MAPKK (MEK) inhibition (PD98059) did not alter U46619-dependent contraction, although ERK1/2 MAPK were activated. By contrast, p38 MAPK inhibition (SB203580) dose-dependently inhibited the contraction, and Western blot analysis showed activation of p38 MAPK in arteries contracted with U46619. Activation of p38 MAPK by U46619 was inhibited by nifedipine and in the absence of extracellular calcium. This study brings new insights in the transduction pathway involved in the contractile response of resistance arteries to TxA2/endoperoxide receptor stimulation. This contraction requires p38 MAPK activation, but did not involve ERK1/2 MAPK activation although both were activated.
Insights
Thromboxane A2 (TxA2) receptor stimulation causes vasoconstriction in rat arteries. This response requires p38 MAPK activation, but not ERK1/2 MAPK, highlighting a key pathway in vascular contraction.
Area of Science:
- Vascular biology
- Cell signaling
- Pharmacology
Background:
- Thromboxane A2 (TxA2) is a key mediator of vasoconstriction and platelet aggregation.
- Mitogen-activated protein kinases (MAPK) are implicated in vascular responses, but their role in resistance arteries under physiological conditions is unclear.
- Understanding TxA2 signaling in resistance arteries is crucial for managing cardiovascular diseases.
Purpose of the Study:
- To investigate the role of MAPK, specifically ERK1/2 and p38, in mediating the contractile response of rat mesenteric resistance arteries to TxA2 receptor stimulation.
- To elucidate the signaling pathways involved in TxA2-induced vasoconstriction under physiological pressure and flow.
Main Methods:
- Isolated rat mesenteric resistance arteries were mounted on an arteriograph and subjected to physiological pressure and flow.
- Concentration-response curves to the stable TxA2 agonist U46619 were generated.
- The effects of specific inhibitors for calcium channels (nifedipine), protein kinase C (GF109203X), tyrosine kinase (tyrphostin A25), MEK (PD98059), and p38 MAPK (SB203580) were assessed.
- Western blot analysis was used to detect MAPK activation.
Main Results:
- TP receptor stimulation with U46619 induced a concentration-dependent contraction in rat resistance arteries.
- Contraction was inhibited by calcium entry blockade and protein kinase C inhibition, but not tyrosine kinase inhibition.
- While both ERK1/2 and p38 MAPK were activated by U46619, only p38 MAPK inhibition (SB203580) significantly reduced the contraction.
- p38 MAPK activation was dependent on calcium influx.
Conclusions:
- The contractile response of rat mesenteric resistance arteries to TxA2 receptor stimulation is critically dependent on p38 MAPK activation.
- ERK1/2 MAPK activation occurs but does not appear to contribute to the contractile response.
- These findings reveal a novel signaling pathway involving p38 MAPK in TxA2-mediated vasoconstriction in resistance arteries.
