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

Overview

Journal Respir Res

Specialty Pulmonary Medicine

Date 2018 Jun 21

PMID 29921306

Citations 27

Authors

Annette D Rieg

Said Suleiman

Carolin Anker

Eva Verjans

Rolf Rossaint

Stefan Uhlig

Christian Martin

Affiliations

Soon will be listed here.

Abstract

Background: Platelet-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).

Methods: In IPLs, PDGF-BB was perfused after or without pre-treatment with imatinib (perfused/nebulised), the effects on the pulmonary arterial pressure (P), the left atrial pressure (P) and the capillary pressure (P) were studied and the precapillary (R) and postcapillary resistance (R) were calculated. Perfusate samples were analysed (ELISA) to detect the PDGF-BB-induced release of prostaglandin metabolites (TXA/PGI). 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 Ca-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.

Results: In IPLs, PDGF-BB increased P, P and R. 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 Ca-channels reduced PDGF-BB-induced contraction, whereas inhibition of ROCK/PKC had no effect. Blocking of EP- and TP-receptors or inhibition of MAP2K-, p38-MAPK-, PI3K-α/γ- and AKT/PKB-signalling prevented PDGF-BB-induced contraction, whereas inhibition of EP only slightly reduced it. Accordingly, PDGF-BB increased TXA in the perfusate, whereas PGI 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.

Conclusions: PDGF-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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References

Sachinidis A, Locher R, Hoppe J, Vetter W . The platelet-derived growth factor isomers, PDGF-AA, PDGF-AB and PDGF-BB, induce contraction of vascular smooth muscle cells by different intracellular mechanisms. FEBS Lett. 1990; 275(1-2):95-8. DOI: 10.1016/0014-5793(90)81447-v. View

Huang J, Ramamurthy S, Lin X, Le Breton G . Cell signalling through thromboxane A2 receptors. Cell Signal. 2004; 16(5):521-33. DOI: 10.1016/j.cellsig.2003.10.008. View

Atzori L, Bannenberg G, Corriga A, Moldeus P, Ryrfeldt A . Sulfur dioxide-induced bronchoconstriction in the isolated perfused and ventilated guinea-pig lung. Respiration. 1992; 59(1):16-21. DOI: 10.1159/000196018. View

Lali F, Hunt A, Turner S, Foxwell B . The pyridinyl imidazole inhibitor SB203580 blocks phosphoinositide-dependent protein kinase activity, protein kinase B phosphorylation, and retinoblastoma hyperphosphorylation in interleukin-2-stimulated T cells independently of p38.... J Biol Chem. 2000; 275(10):7395-402. DOI: 10.1074/jbc.275.10.7395. View

Beazely M, Weerapura M, Macdonald J . Abelson tyrosine kinase links PDGFbeta receptor activation to cytoskeletal regulation of NMDA receptors in CA1 hippocampal neurons. Mol Brain. 2008; 1:20. PMC: 2651131. DOI: 10.1186/1756-6606-1-20. View

Pollack I, Kawecki S . The effect of calphostin C, a potent photodependent protein kinase C inhibitor, on the proliferation of glioma cells in vitro. J Neurooncol. 1997; 31(3):255-66. DOI: 10.1023/a:1005729626354. View

Walch L, de Montpreville V, Brink C, Norel X . Prostanoid EP(1)- and TP-receptors involved in the contraction of human pulmonary veins. Br J Pharmacol. 2001; 134(8):1671-8. PMC: 1572903. DOI: 10.1038/sj.bjp.0704423. View

Markovic T, Jakopin Z, Dolenc M, Mlinaric-Rascan I . Structural features of subtype-selective EP receptor modulators. Drug Discov Today. 2016; 22(1):57-71. DOI: 10.1016/j.drudis.2016.08.003. View

Sasahara T, Yayama K, Okamoto H . p38 mitogen-activated protein kinase mediates hyperosmolarity-induced vasoconstriction through myosin light chain phosphorylation and actin polymerization in rat aorta. Biol Pharm Bull. 2013; 36(11):1849-56. DOI: 10.1248/bpb.b13-00563. View

10.

Rieg A, Rossaint R, Verjans E, Maihofer N, Uhlig S, Martin C . Levosimendan Relaxes Pulmonary Arteries and Veins in Precision-Cut Lung Slices - The Role of KATP-Channels, cAMP and cGMP. PLoS One. 2013; 8(6):e66195. PMC: 3688856. DOI: 10.1371/journal.pone.0066195. View

11.

Bonnet S, Archer S . Potassium channel diversity in the pulmonary arteries and pulmonary veins: implications for regulation of the pulmonary vasculature in health and during pulmonary hypertension. Pharmacol Ther. 2007; 115(1):56-69. DOI: 10.1016/j.pharmthera.2007.03.014. View

12.

Ohanian V, Gatfield K, Ohanian J . Role of the actin cytoskeleton in G-protein-coupled receptor activation of PYK2 and paxillin in vascular smooth muscle. Hypertension. 2005; 46(1):93-9. DOI: 10.1161/01.HYP.0000167990.82235.3c. View

13.

Liu H, Sperelakis N . Tyrosine kinases modulate the activity of single L-type calcium channels in vascular smooth muscle cells from rat portal vein. Can J Physiol Pharmacol. 1997; 75(9):1063-8. View

14.

Huang W, Metcalf C, Sundaramoorthi R, Wang Y, Zou D, Thomas R . Discovery of 3-[2-(imidazo[1,2-b]pyridazin-3-yl)ethynyl]-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzamide (AP24534), a potent, orally active pan-inhibitor of breakpoint cluster region-abelson (BCR-ABL) kinase.... J Med Chem. 2010; 53(12):4701-19. DOI: 10.1021/jm100395q. View

15.

Matsuoka T, Narumiya S . Prostaglandin receptor signaling in disease. ScientificWorldJournal. 2007; 7:1329-47. PMC: 5901339. DOI: 10.1100/tsw.2007.182. View

16.

Abe K, Toba M, Alzoubi A, Koubsky K, Ito M, Ota H . Tyrosine kinase inhibitors are potent acute pulmonary vasodilators in rats. Am J Respir Cell Mol Biol. 2011; 45(4):804-8. PMC: 5460892. DOI: 10.1165/rcmb.2010-0371OC. View

17.

Thimmaiah K, Easton J, Germain G, Morton C, Kamath S, Buolamwini J . Identification of N10-substituted phenoxazines as potent and specific inhibitors of Akt signaling. J Biol Chem. 2005; 280(36):31924-35. DOI: 10.1074/jbc.M507057200. View

18.

Berk B, Alexander R, Brock T, Gimbrone Jr M, Webb R . Vasoconstriction: a new activity for platelet-derived growth factor. Science. 1986; 232(4746):87-90. DOI: 10.1126/science.3485309. View

19.

Filep J, Fournier A . Endothelin-1-induced myocardial ischaemia and oedema in the rat: involvement of the ETA receptor, platelet-activating factor and thromboxane A2. Br J Pharmacol. 1994; 112(3):963-71. PMC: 1910206. DOI: 10.1111/j.1476-5381.1994.tb13175.x. View

20.

Barnes P, Liu S . Regulation of pulmonary vascular tone. Pharmacol Rev. 1995; 47(1):87-131. View