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

Abstract

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.

LncRNA H19 promotes the proliferation of pulmonary artery smooth muscle cells through AT1R via sponging let-7b in monocrotaline-induced pulmonary arterial hypertension

“…How these cytokines lead to PAH remained elusive. Similar to previous studies [9], our results showed that PDGF-BB activated the proliferation of PASMCs. The relationship between inflammatory cytokines and H19 is controversial.…”

“…Previous studies suggested that the lungs from PAH patients are characterized by the infiltration of inflammatory cells and an increase in pro-inflammatory cytokines, such as interleukin-1 alpha (IL-1α), interleukin-1 beta (IL-1β), platelet derived growth factors beta polypeptide b (PDGF-BB), interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), and tumor necrosis factor-alpha (TNF-α) [6–9]. Moreover, PDGF-BB promotes PASMCs proliferation [9, 10]. In addition to inflammation, the renin-angiotensin system (RAS) also plays an important role in PAH pathogenesis.…”

An Analysis of the Anti‐Neuropathic Effects of Qi She Pill Based on Network Pharmacology

“…A neuroactive ligand-receptor interaction signaling pathway is a collection of receptor ligands on the plasma membrane that are associated with intracellular and extracellular signaling pathways and are closely related physiologically to neurological function [38]. Key molecules in the calcium signaling pathway have a variety of biological functions, among which calcium ions play an important role in maintaining biopotential [39], maintaining normal nerve conduction function [40], and regulating physiological actions including intracellular enzyme activity, muscle contraction and relaxation [41], nervous system function [42], stimulation and secretion-coupled participation [43], glucose metabolism [44], and prostaglandin [45] and insulin synthesis [46].…”

miRNA-PDGFRB/HIF1A-lncRNA CTEPHA1 Network Plays Important Roles in the Mechanism of Chronic Thromboembolic Pulmonary Hypertension

“…For example, in the related downstream pathway of PDGFRB, the PDGF-BB/PDGFR genes were associated with the regulation of pulmonary vascular tension through the mechanism of prostaglandin formation, calcium increase, MAPK-or PI3K/Akt/mTOR signal transduction, and actin remodeling activation. 28) NBL1 inhibited the proliferation of human pulmonary vascular smooth muscle cells (PASMC) induced by PDGF-BB through blocking PDGF beta -p38MAPK pathway. 29) In the CTEPH-related Pathway-Net of our study, the MAPK and calciumsignaling pathways were at the core of the network (Degree = 31, 12), which is consistent with the abovementioned report.…”