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, 121 (18), 2045-66

Basic Science of Pulmonary Arterial Hypertension for Clinicians: New Concepts and Experimental Therapies


Basic Science of Pulmonary Arterial Hypertension for Clinicians: New Concepts and Experimental Therapies

Stephen L Archer et al. Circulation.

Conflict of interest statement

Conflict of Interest Disclosure: The authors have no conflict of interest to disclose other than the acknowledged grant support. All authors had full access to the manuscript and approved the final version.


Figure 1
Figure 1. Histology of PAH
Upper panels show plexiform lesions. Left panel- note the evidence of cell proliferation (red is proliferating cell nuclear antigen, green is smooth muscle actin, blue is DAPI). Lower panels show medial hypertrophy, intimal fibrosis and adventitial proliferation. Figure and legend contributed by Dr. S.L. Archer
Figure 2
Figure 2. Formation of complex and plexiform lesions in PAH
Transformation of an arteriole, into a complex vascular lesion with near total or total lumen obliteration, usually occurs at a vessel bifurcation. The concept depicted is one of initial apoptosis of cells forming the endothelial monolayer (left). Disorganized endovascular angiogenesis results from proliferation of phenotypically abnormal cells due to 1) phagocytosis of apoptotic monolayer endothelial cells by neighboring endothelial cells 2) activation of stem cell-like endothelial cells or 3) attachment of bone-marrow derived “repair cells” to the injured endothelium. Bone marrow participation in the formation of these lesions is postulated because megakaryocytes, mast cells and dendritic cells can be released and attach to the injured vessel. Perivascular lymphocytes may cluster in the lymphatics adjacent to the adventitia. The lesion also shows a dysregulated matrix. Growth factors released by megakaryocytes and mast cells may contribute to the angiogenic growth and T and B-lymphocytes may reflect a local immune response. The table insert lists the phenotypic changes seen in plexiform lesions. Figure and legend contributed by Dr. Norbert Voelkel, Virginia Commonwealth University, Richmond, VA.
Figure 3
Figure 3. PAH is a panvasculopathy
Abnormalities can be seen at each level of the small pulmonary arteries, beginning in the blood and travelling outward to the adventitia. While most of these abnormalities are likely secondary (rather than being the initiating cause of PAH), they nonetheless offer interesting therapeutic targets Contributed by Dr. S.L. Archer
Figure 4
Figure 4. Serotonin (5-HT) abnormalities in PAH
Increased bioavailability of serotonin during progression of PAH results from an increased release of serotonin from platelets and from an increased synthesis of serotonin by endothelial cells which produce serotonin and express tryptophan hydroxylase-1 (TPH1), the key enzyme controling 5-HT synthesis. Overexpression of 5-HTT (SERT) by PASMC is responsible for the increased mitogenic effect of serotonin on these cells. 5-HT receptors, including 5-HT1B/1D and 5-HT2A receptors mediate 5-HT-induced PA contraction of pulmonary vessels. 5-HT2A receptors located on platelets potentiate the aggregation response to various platelet activators. 5-HT2B receptors expressed by PASMC are also involved in the pulmonary vascular remodeling process. Figure and legend contributed by Dr. Serge Adnot, Département de Physiologie, Hôpital Henri Mondor, CRETEIL, FRANCE
Figure 5
Figure 5. The endothelium and vasodilator/antiproliferative pathways
Nitric oxide (NO), generated from L-arginine, and natriuretic peptides stimulate production of cyclic guanosine monophosphate (GMP). cGMP causes vasorelaxation and inhibits proliferation of vascular SMC. Phosphodiesterase type 5 (PDE5) inhibitors (e.g. sildenafil) enhance this vasodilatory mechanism by preventing cGMP degradation. Prostacylin from endothelial cells also promotes relaxation and inhibits cell proliferation, via a cyclic AMP-dependent mechanism. Endothelin is a potent vasoconstrictor and stimulates proliferation via ETA receptors on SMC; while stimulating NO and prostacylin release via endothelial ETB receptors. Adrenomedullin (AM) and vasoactive intestinal polypeptide (VIP) are additional endothelial-derived, cAMP-dependent vasodilators that are dysregulated in PAH. Contributed by Dr. Martin Wilkins
Figure 6
Figure 6. BMPR2 mutations-a genetic basis for familial PAH
BMPR2 mutations are found throughout the gene, and a universal functional consequence of these mutations has not been identified. Best studied is BMPR1 signaling through SMAD transcription factors. Mutations leading to loss of SMAD signaling decreases cell differentiation, enhance vascular tone, increase TGF-β signaling and likely increase proliferation. Signaling through XIAP (X-linked inhibitor of apoptosis), also requiring BMPR1, can impact both NFkB and MAPK pathways, leading to increased MAPK phosphorylation and presumably pro-inflammatory signaling. BMPR2 has a long, evolutionarily conserved cytoplasmic tail domain unique in the TGF-beta superfamily, which binds SRC, RACK1, and LIMK1. BMPR2 mutation in vivo leads to decreased Cofilin (Cfl1) phosphorylation by LIMK1, with the effect both of alterations in F-actin organization and defects in glucocorticoid receptor (GR) nuclear translocation. Figure and legend contributed by Drs. James West and John H. Newman, Pulmonary Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee.
Figure 7
Figure 7. Mitochondrial metabolism in PAH
In aerobic metabolism, PDK is inactive, PDH is active and electron donors (mitochondrial NADH and FADH) produced by the TCA (Krebs') cycle pass electrons down a redox-potential gradient in the electron transport chain (ETC) to molecular O2. This electron flux powers H+ ion extrusion, creating the proton-motive force responsible for creating the mitochondria's negative membrane potential (ΔΨm) and powering F1Fo-ATP-synthase. Side reactions between semiquinones and molecular O2, accounting for ∼3% of net electron flux, create superoxide anion in proportion to PO2. Superoxide dismutase (SOD2) rapidly converts superoxide anion (produced at complexes I and III) to H2O2, which serves as a redox messenger signaling “normoxia”. In hypoxia (and PAH and cancer) there is activation of HIF-1α and PDK, which inhibits PDH shifting metabolism toward glycolysis. Therapeutic implications: Dichloroacetate which inactivates PDK by causing conformational changes in its nucleotide- and lipoyl-binding pockets60) regresses experimental PAH,. Contributed by Dr. Stephen L. Archer
Figure 8
Figure 8. Receptor tyrosine kinases and their inhibitors
This complex kinase cascade offers many therapeutic targets to treat PAH. Abbreviations: ATF, activating transcription factor; BAD, BCL-XL/BCL-2 associated death promoter; c-kit, CD117; DAG, diacyl glycerol; EGF-R, epidermal growth factor receptor; ErbB1,2 epidermal growth factor receptor; ERK, extracellular signal-regulated kinase; flt3, fms-like tyrosine kinase receptor-3; GSK, glycogen synthase kinase; JAK, Janus kinase; JNK, Jun N-terminal kinase; MEF, myocyte-specific enhancer-binding nuclear factor; MEK, mitogen-activated protein kinase/ERK kinase; MERM, ezrin/radixin/moezin family of cytoskeletal linkers; mTOR, mammalian target of rapamycin; NHERF, sodium-hydrogen exchange regulatory factor; P, phosphotyrosine; p70S6K, p70 ribosomal S6 kinase; PIP2, phosphatidylinositol-4,5-bisphosphate; PIP3, phosphatidylinositol-3,4,5-trisphosphate; PKB, protein kinase B; PKC, protein kinase C; PLC, phospholipase C; SOS, Son of Sevenless; STAT, signal transducer and activator of transcription; PDGF-R, platelet-derived growth factor receptor: PDK, phosphoinositide-dependent kinase; PI3K, phosphoinositide-3 kinase; PKB, protein kinase B; PKC, protein kinase C; PLC, phospholipase C; SHP, Src homology 2-containing protein tyrosine phosphatase; VEGF-R, vascular endothelial growth factor receptor. Figure and legend contributed by Dr. Ralph Schermuly, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim, Germany
Figure 9
Figure 9. Ion Channels in PAH
Schematic depiction of the cellular mechanisms linked with the vasoconstriction and remodeling in pulmonary endothelial (PAEC) and PASMC in PAH. Central themes of interest for the development of PAH include: 1) impaired ion channel expression and function in PASMC (Kv, VDCC, SOC, ROC), 2) increased cytosolic calcium ([Ca2+]cyt) in PASMC (mediated by ion channel function and receptor stimulation), 3) altered signaling via membrane receptors (GPCR, TIE-2, BMPR, RTK) and transporters (i.e., SERT) in endothelial cells and PASMC, 4) changes in redox status, 5) enhanced production of vasoconstrictor or mitogenic factors, and 6) viral signaling via GPCR and RTK. Paracrine interactions between PAEC and PASMC are noteworthy. Abbreviations: Ang-1, angiopoietin-1; ET-1, endothelin-1; GPCR, G protein-coupled receptor; 5-HT, serotonin; MAPK, mitogen-activated protein kinase; NO, nitric oxide; PDGF, platelet-derived growth factor; PGI2, prostaglandin I2; ROC, receptor-operated Ca2+ channels; ROCK, Rho-associated kinase; ROS, reactive oxygen species; RTK, receptor tyrosine kinase; SERT, 5-HT transporter; SOC, store-operated Ca2+ channels; SR, sarcoplasmic reticulum; VDCC, voltage-dependent Ca2+ channels. Figure and Legend Contributed by Drs. Carmelle Remillard and Jason Yuan, University of California, San Diego
Figure 10
Figure 10. Disordered Elastin metabolism and deposition in PAH
Elastase degrades elastin and other components of the extracellular matrix thereby releasing bound growth factors, that are both mito- and motogenic for PASMC. Heightened elastase activity also activates matrix metalloproteinases (MMPs), which upregulate the glycoprotein tenascin-C. When tenascin-C binds cell surface integrins, such as alpha-v β3 on PASMC, these integrins cluster and cell shape changes in a way that clusters and activates growth factor receptors and increases cell survival signals. Thus, pathway activation causes both release of growth factors and activation of their receptors. Transmission of cell survival signals occurs even in the absence of ligand (growth factor) binding. Blocking elastase activity or growth factor receptors can therefore arrest progression of PASMC by blocking proliferation and induce regression by enhancing apoptosis. Figure and legend contributed by Marlene Rabinovitch, Stanford University, Palo Alto, CA.
Figure 11
Figure 11. The role of inflammation in the pathogenesis of PAH
Initial inflammatory stimuli can occur in the form of infectious or foreign antigens or autoimmune disease, leading to an appropriate, but potentially excessive, immune response. The host immune response to these varied stimuli results in the release of pro-inflammatory cytokines, which can recruit bone marrow-derived cells, stimulation of resident inflammatory cells, and endothelial cell dysfunction. Endothelial cell injury and the cellular response can increase endovascular thrombosis. A network of cytokines released by the inflammatory and endothelial cells can also cause aberrant PASMC proliferation. The triad of endothelial cell proliferation, PASMC proliferation, and thrombus formation contributes to PAH. Pro-inflammatory cytokines and cell-cell interactions can potentially be therapeutically targeted. Abbreviations: EGF: epidermal growth factor; HIMF: hypoxia induced mitogenic factor, also called RELMa and FIZZ1; NO: nitric oxide; PDGF: platelet derived growth factor; RANTES; TNFα: tumor necrosis factor-alpha. Figure and legend contributed by Drs. Brian Graham and Rubin Tuder, University of Colorado at Denver.
Figure 12
Figure 12. Cellular Basis for Pulmonary Vascular Remodeling-lessons from hypoxia
Fibroblasts, monocytes and fibrocytes play critical roles in orchestrating hypoxia-induced pulmonary vascular remodeling. Hypoxia or hypoxia-associated stimuli increase production by resident fibroblasts (and probably PASMC) of chemokines/cytokines including: monocyte chemoattractant protein (MCP)-1, stromal cell-derived factor (SDF)-1, fractalkine (CX3CL1), RANTES, VEGF, osteopontin (OPN) and endothelin. These and other factors stimulate recruitment of monocytes and monocyte-derived mesenchymal precursors (fibrocytes) to the vessel wall. Upregulation of monocyte receptors for these ligands (CCR2, CXCR4, CX3CR1, VEGFR-1 and ETR-A) occurs. Monocytes are retained in the vessel wall by the upregulation of adhesion molecules on fibroblasts, including vascular cell adhesion molecule (VCAM), intracellular adhesion molecule (ICAM) and OPN. As monocytes and fibrocytes accumulate in the vessel wall, they exert potent effects on the proliferative, migratory, matrix-producing and contractile capabilities of resident fibroblasts and PASMC through the secretion of TGF-β, PDGF-A and B, EGF, IL-6, IGF-1, MMP-9 and others. In addition, these cells produce potent proangiogenic molecules such as VEGF, S100A4, βFGF that likely play roles in stimulating further angiogenesis in the vessel wall. Figure and legend contributed by Kurt Stenmark, University of Colorado at Denver.

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