Spatio-Temporal Diversity of Apoptosis Within the Vascular Wall in Pulmonary Arterial Hypertension
2006; Lippincott Williams & Wilkins; Volume: 98; Issue: 2 Linguagem: Inglês
10.1161/01.res.0000204572.65400.a5
ISSN1524-4571
Autores Tópico(s)Renin-Angiotensin System Studies
ResumoHomeCirculation ResearchVol. 98, No. 2Spatio-Temporal Diversity of Apoptosis Within the Vascular Wall in Pulmonary Arterial Hypertension Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBSpatio-Temporal Diversity of Apoptosis Within the Vascular Wall in Pulmonary Arterial HypertensionHeterogeneous BMP Signaling May Have Therapeutic Implications Evangelos D. Michelakis Evangelos D. MichelakisEvangelos D. Michelakis From the Pulmonary Hypertension Program, University of Alberta, Edmonton, Canada. Originally published3 Feb 2006https://doi.org/10.1161/01.RES.0000204572.65400.a5Circulation Research. 2006;98:172–175"The temptation to form premature theories is the bane of our profession."— Sherlock HolmesAlthough pulmonary arterial hypertension (PAH) was originally thought to be a disease of increased pulmonary arterial (PA) tone, we now know that vasoconstriction is important only in a minority of patients.1 PAH is characterized by increased proliferation of PA endothelial cells (PAECs) and PA smooth muscle cells (PASMCs), leading to narrowing or even obliteration of the PA lumen, increased pulmonary vascular resistance (PVR), right ventricular failure and premature death.1Voelkel and Tuder suggested that the proliferative remodeling in the PAs resembles cancer.2 Several features, in addition to excessive proliferation, make this hypothesis attractive. For example, as in cancer, the development of PAH appears to result from a "multiple-hit" mechanism, where environmental factors (virus, inflammation, anorexigens, shunt-induced shear stress, etc) interact with a genetic predisposition (loss-of-function mutations in the bone morphogenetic protein receptor II, BMPR-II) culminating in disease.1 That PAH is characterized by a cancer-like apoptosis resistance is supported by recent reports that proapoptotic therapies can reverse PAH, similarly to cancer, where proapoptotic chemotherapies are the mainstay of treatment. Several experimental PAH treatments (including dichloroacetate,3 simvastatin,4 sildenafil,5 imatinib,6 anti-survivin,7 and K+ channel replacement gene therapies8) induce apoptosis of PASMCs, leading to reversal of vascular remodeling and PAH. In sharp contrast, strategies designed to promote survival and inhibit apoptosis of PAECs (cell-based gene transfer of angiopoietin-19 or eNOS,10 caspase inhibitors11) also improve PAH, particularly at early stages. These apparently conflicting reports can be rationalized by the hypothesis that vascular apoptosis is regulated in a compartment-specific manner.The role of apoptosis in the pathogenesis of PAH is also supported by the discovery that mutations in BMPR-II predispose patients to familial PAH.12 Like most mediators involved in embryological development, BMPs are important regulators of apoptosis. It was initially assumed that loss-of-function BMPR-II mutations would suppress apoptosis and increase proliferation in the PA wall, perhaps fully explaining the vascular remodeling in PAH. However it is now recognized that although most familial PAH patients carry mutations, they are found in only &10% of patients with sporadic idiopathic PAH (iPAH) and their presence confers only a 15% to 20% chance of PAH in a carrier's lifetime.12 Nevertheless, this discovery offered new insights into the biology of PAH.BMP Signaling in the Pulmonary CirculationBMP4 inhibits growth of PASMC from normal but not iPAH patients13 and, similarly, BMP2 and -7 induce more apoptosis in normal than in iPAH PASMCs.14 Interestingly, these human data are not supported by transgenic models. Heterozygous knockout mice lacking exons 4 to 5 of the BMPR-II gene have only mild pulmonary hypertension at baseline and, surprisingly, after exposure to chronic hypoxia the muscularization of distal PAs is not different than in wild mice.15 A new transgenic model, where a dominant-negative BMPR-II gene from a familial PAH patient was conditionally overexpressed in SMCs, does have the predicted increase in PA pressure, but it too lacks PA muscularization.16 The dissociation of hemodynamics from vascular remodeling in these models and the species-specific effects of BMPs in PASMCs raise questions regarding the clinical relevance of some mice models and casts doubt on the central/obligatory importance of PASMC as the primary targets of abnormal BMP signaling. Nevertheless, the BMP axis is highly active in PAs (more so in the PAECs than in PASMCs) and may be involved in the pathogenesis of PAH through means beyond those related to BMPR-II mutations.1 Surprisingly, studies on the direct role of the BMP axis on human PAEC are lacking, despite the recognition that endothelial dysfunction is a critical and early event in PAH. Therefore, the work presented in this issue of Circulation Research by Dr Stewart's group on BMP signaling in human PAECs is welcome.17They show that BMP2 and -7 inhibit apoptosis (induced by serum-deprivation or TNF-exposure) in normal human PAECs. Also, inhibition of BMPR-II expression by 50% using siRNA increases basal PAEC apoptosis 3-fold. More importantly, they studied circulating endothelial precursor cells (EPCs) from both normal volunteers and 15 patients with iPAH. The level of BMPR-II expression was similar in normal and iPAH EPCs, but their response to exogenous BMP2 was quite different. BMP2 inhibited apoptosis in normal but not iPAH EPCs (P<0.05). Interestingly, the severity of PAH (based on invasively measured mean PA pressure) showed a positive (although weak) correlation with the response of EPC to BMP2. They conclude that loss-of-function mutations in BMPR-II could increase PAEC apoptosis and initiate PAH.Dr Stewart and his team are to be congratulated for their efforts to present data from PAH patients and correlate in vitro data with clinical parameters. Translational investigator-driven research of this kind is very much needed but is often challenging because of ethical and logistical complexities of studying seriously ill patients. Nonetheless, this study does have some limitations. BMPR-II genotyping was not performed, and the worthy attempt to correlate a hemodynamic clinical parameter with EPC apoptosis was compromised by lack of control for the type of therapy and patient demographics. Moreover, the use of PA pressure rather than PVR is suboptimal, as cardiac output is not accounted for. Despite these limitations, the data significantly advance our knowledge on the primary role of PAECs in the pathogenesis of PAH and, as discussed below, inspire for the proposal of an apoptosis-based theory of PAH.More work is required to expand this new field that the authors open with their work. First, confirmation of their findings in larger cohorts of patients is needed. Second, work is also required to reveal the role of EPCs in the biology of PAH. In the meantime, the in vitro response of circulating EPCs to therapies targeting the BMP axis or other apoptotic pathways might evolve as a predictor of the clinical response to such therapies in individual patients. Measuring the function and/or numbers of circulating EPCs might also prove to be a biomarker that could detect early PAH or be used in risk-stratifying patients with advanced disease.18Does the current article explain the restriction of the vascular pathology in PAH to the pulmonary circulation? The authors suggest that the increased shear stress in the pulmonary microvessels (the lung is the only organ that experiences the entire cardiac output) makes the PAECs more vulnerable than systemic ECs to apoptosis. A basally elevated shear stress in the pulmonary circulation might also allow for a selection pressure and emergence of apoptosis-resistant PAECs, which localizes proliferative vascular remodeling. This concept is supported by elegant experiments describing the emergence of apoptosis-resistant PAECs (expressing survivin, an inhibitor of apoptosis and tumor marker), after shear-stress–induced apoptosis in vitro.19Furthermore, a significant difference between the pulmonary and systemic microvessels is their exposure to very different redox environments, because the lung microvessels are uniquely exposed to much higher PO2 and thus oxidative stress than systemic vessels. Weir and Archer have shown that such redox differences provide the basis for the fact that hypoxic pulmonary vasoconstriction is unique to the pulmonary circulation.20 The observation that the BMP axis can be enhanced by redox mechanisms in EC (H2O2 directly increases BMP2 expression21) suggests that it can be enhanced locally in the pulmonary circulation despite the expression of BMP receptors (normal or mutated) throughout the vasculature.An Apoptosis-Based Theory for the Development of PAH: Being at the Right Place the Right TimeThe Toronto group's report does allow development of a testable hypothesis for the pathogenesis of PAH in humans. Central to this hypothesis is the fact that apoptosis shows a spatio-temporal diversity within the vascular wall as PAH develops. An abnormality in the BMP axis, inherited or acquired, will promote the apoptosis of PAECs, particularly in response to injury (viral infection, increased shear stress, etc). Initial PAEC death will cause loss of small capillaries (which are essentially PAEC tubes), increasing the flow and shear stress in the remaining vessels, amplifying the effect. The emergence of apoptosis-resistant PAECs, expressing survivin,19 will lead to the proliferation in the intima and in plexogenic lesions. At the same time, loss of PAECs would allow for exposure of PASMCs to circulating growth factors that are normally excluded, except in vascular injury. Such a factor, PDGF, has been shown to induce the expression of survivin in vascular SMCs.22 Survivin itself also induces the production of PDGF in human vascular SMCs.23 This positive feedback allows for amplification of the survivin pathway and thus the resistance to apoptosis. Indeed, patients and animals with PAH, but not normal controls, show high levels of survivin expression in PAs.7 Selective delivery of a dominant-negative construct to the small PAs (using an inhaled adenovirus) induces apoptosis, decreases proliferation in the media, and reverses PAH.7 Also, inhibition of the PDGF pathway either by fish oil24 or imatinib6 reverses PAH in animals.In summary, early PAH is characterized by increased apoptosis in the endothelial layer. In contrast, late PAH is characterized by suppressed apoptosis and increased proliferation in both the intima and the media. This view has potential therapeutic implications (Figure). Patients in early stages of PAH may benefit more from antiapoptotic approaches, whereas patients presenting in late stages (which unfortunately represent the majority) will benefit from proapoptotic strategies. Patients with intermediate stages of PAH might require cell-specific or vascular compartment–specific therapies. PAH in individual patients might need to be properly "staged" to select the appropriate pro- or antiapoptotic therapies, much like in cancer. Unfortunately, open lung biopsies carry a significant risk and are rarely used in PAH, although catheter-based approaches have shown promise in large animal models.25 The direct assessment of apoptosis within the pulmonary circulation in vivo will be very important in this approach, and this is already used in cancer. Emerging molecular imaging techniques show promise for the in vivo assessment of vascular apoptosis in humans.26The proposal of an apoptosis theory for PAH, inspired by recent publications including the one under discussion, might seem premature but perhaps can be more kindly received in light of Einstein's view that "it is theory that decides what can be observed."Download figureDownload PowerPointAn apoptosis-based theory for the development of pulmonary arterial hypertension and its therapeutic implications.The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.This work was supported by the Canadian Institutes for Health Research, the Heart and Stroke Foundation, and the Alberta Heritage Foundation for Medical Research.FootnotesCorrespondence to Evangelos D. Michelakis, MD, FACC, FAHA, Director, Pulmonary Hypertension Program, University of Alberta, Canada Research Chair in Pulmonary Hypertension, Edmonton, Alberta T6G2B7, Canada. E-mail [email protected] References 1 Humbert M, Morrell NW, Archer SL, Stenmark KR, MacLean MR, Lang IM, Christman BW, Weir EK, Eickelberg O, Voelkel NF, Rabinovitch M. Cellular and molecular pathobiology of pulmonary arterial hypertension. J Am Coll Cardiol. 2004; 43: 13S–24S.CrossrefMedlineGoogle Scholar2 Voelkel NF, Cool C, Lee SD, Wright L, Geraci MW, Tuder RM. Primary pulmonary hypertension between inflammation and cancer. Chest. 1998; 114: 225S–230S.CrossrefMedlineGoogle Scholar3 McMurtry MS, Bonnet S, Wu X, Dyck JR, Haromy A, Hashimoto K, Michelakis ED. Dichloroacetate prevents and reverses pulmonary hypertension by inducing pulmonary artery smooth muscle cell apoptosis. Circ Res. 2004; 95: 830–840.LinkGoogle Scholar4 Nishimura T, Vaszar LT, Faul JL, Zhao G, Berry GJ, Shi L, Qiu D, Benson G, Pearl RG, Kao PN. Simvastatin rescues rats from fatal pulmonary hypertension by inducing apoptosis of neointimal smooth muscle cells. Circulation. 2003; 108: 1640–1645.LinkGoogle Scholar5 Wharton J, Strange JW, Moller GM, Growcott EJ, Ren X, Franklyn AP, Phillips SC, Wilkins MR. Antiproliferative effects of phosphodiesterase type 5 inhibition in human pulmonary artery cells. Am J Respir Crit Care Med. 2005; 172: 105–113.CrossrefMedlineGoogle Scholar6 Schermuly RT, Dony E, Ghofrani HA, Pullamsetti S, Savai R, Roth M, Sydykov A, Lai YJ, Weissmann N, Seeger W, Grimminger F. Reversal of experimental pulmonary hypertension by PDGF inhibition. J Clin Invest. 2005; 115: 2811–2821.CrossrefMedlineGoogle Scholar7 McMurtry MS, Archer SL, Altieri DC, Bonnet S, Haromy A, Harry G, Bonnet S, Puttagunta L, Michelakis ED. Gene therapy targeting survivin selectively induces pulmonary vascular apoptosis and reverses pulmonary arterial hypertension. J Clin Invest. 2005; 115: 1479–1491.CrossrefMedlineGoogle Scholar8 Pozeg ZI, Michelakis ED, McMurtry MS, Thebaud B, Wu XC, Dyck JR, Hashimoto K, Wang S, Moudgil R, Harry G, Sultanian R, Koshal A, Archer SL. In vivo gene transfer of the O2-sensitive potassium channel Kv1.5 reduces pulmonary hypertension and restores hypoxic pulmonary vasoconstriction in chronically hypoxic rats. Circulation. 2003; 107: 2037–2044.LinkGoogle Scholar9 Zhao YD, Campbell AI, Robb M, Ng D, Stewart DJ. Protective role of angiopoietin-1 in experimental pulmonary hypertension. Circ Res. 2003; 92: 984–991.LinkGoogle Scholar10 Zhao YD, Courtman DW, Deng Y, Kugathasan L, Zhang Q, Stewart DJ. Rescue of monocrotaline-induced pulmonary arterial hypertension using bone marrow-derived endothelial-like progenitor cells: efficacy of combined cell and eNOS gene therapy in established disease. Circ Res. 2005; 96: 442–450.LinkGoogle Scholar11 Taraseviciene-Stewart L, Kasahara Y, Alger L, Hirth P, Mc Mahon G, Waltenberger J, Voelkel NF, Tuder RM. Inhibition of the VEGF receptor 2 combined with chronic hypoxia causes cell death-dependent pulmonary endothelial cell proliferation and severe pulmonary hypertension. Faseb J. 2001; 15: 427–438.CrossrefMedlineGoogle Scholar12 Newman JH, Trembath RC, Morse JA, Grunig E, Loyd JE, Adnot S, Coccolo F, Ventura C, Phillips JA 3rd, Knowles JA, Janssen B, Eickelberg O, Eddahibi S, Herve P, Nichols WC, Elliott G. Genetic basis of pulmonary arterial hypertension: current understanding and future directions. J Am Coll Cardiol. 2004; 43: 33S–39S.CrossrefMedlineGoogle Scholar13 Morrell NW, Yang X, Upton PD, Jourdan KB, Morgan N, Sheares KK, Trembath RC. Altered growth responses of pulmonary artery smooth muscle cells from patients with primary pulmonary hypertension to transforming growth factor-beta(1) and bone morphogenetic proteins. Circulation. 2001; 104: 790–795.CrossrefMedlineGoogle Scholar14 Zhang S, Fantozzi I, Tigno DD, Yi ES, Platoshyn O, Thistlethwaite PA, Kriett JM, Yung G, Rubin LJ, Yuan JX. Bone morphogenetic proteins induce apoptosis in human pulmonary vascular smooth muscle cells. Am J Physiol Lung Cell Mol Physiol. 2003; 285: L740–L754.CrossrefMedlineGoogle Scholar15 Beppu H, Ichinose F, Kawai N, Jones RC, Yu PB, Zapol WM, Miyazono K, Li E, Bloch KD. BMPR-II heterozygous mice have mild pulmonary hypertension and an impaired pulmonary vascular remodeling response to prolonged hypoxia. Am J Physiol Lung Cell Mol Physiol. 2004; 287: L1241–L1247.CrossrefMedlineGoogle Scholar16 West J, Fagan K, Steudel W, Fouty B, Lane K, Harral J, Hoedt-Miller M, Tada Y, Ozimek J, Tuder R, Rodman DM. Pulmonary hypertension in transgenic mice expressing a dominant-negative BMPRII gene in smooth muscle. Circ Res. 2004; 94: 1109–1114.LinkGoogle Scholar17 Teichert-Kuliszewska K, Kutryk MJ, Kuliszewski MA, Karoubi G, Courtman DW, Zucco L, Granton J, Stewart DJ. Bone morphogenetic protein receptor-2 signaling promotes pulmonary arterial endothelial cell survival: implications for loss-of-function mutations in the pathogenesis of pulmonary hypertension. Circ Res. 2006; 98: 209–217.LinkGoogle Scholar18 Bull TM, Coldren CD, Moore M, Sotto-Santiago SM, Pham DV, Nana-Sinkam SP, Voelkel NF, Geraci MW. Gene microarray analysis of peripheral blood cells in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2004; 170: 911–919.CrossrefMedlineGoogle Scholar19 Sakao S, Taraseviciene-Stewart L, Lee JD, Wood K, Cool CD, Voelkel NF. Initial apoptosis is followed by increased proliferation of apoptosis-resistant endothelial cells. Faseb J. 2005; 19: 1178–1180.CrossrefMedlineGoogle Scholar20 Weir EK, Lopez-Barneo J, Buckler KJ, Archer SL. Acute oxygen-sensing mechanisms. N Engl J Med. 2005; 353: 2042–2055.CrossrefMedlineGoogle Scholar21 Csiszar A, Smith KE, Koller A, Kaley G, Edwards JG, Ungvari Z. Regulation of bone morphogenetic protein-2 expression in endothelial cells: role of nuclear factor-kappaB activation by tumor necrosis factor-alpha, H2O2, and high intravascular pressure. Circulation. 2005; 111: 2364–2372.LinkGoogle Scholar22 Blanc-Brude OP, Yu J, Simosa H, Conte MS, Sessa WC, Altieri DC. Inhibitor of apoptosis protein survivin regulates vascular injury. Nat Med. 2002; 8: 987–994.CrossrefMedlineGoogle Scholar23 Wang GJ, Sui XX, Simosa HF, Jain MK, Altieri DC, Conte MS. Regulation of vein graft hyperplasia by survivin, an inhibitor of apoptosis protein. Arterioscler Thromb Vasc Biol. 2005; 25: 2081–2087.LinkGoogle Scholar24 Archer SL, Johnson GJ, Gebhard RL, Castleman WL, Levine AS, Westcott JY, Voelkel NF, Nelson DP, Weir EK. Effect of dietary fish oil on lung lipid profile and hypoxic pulmonary hypertension. J Appl Physiol. 1989; 66: 1662–1673.CrossrefMedlineGoogle Scholar25 Rothman A, Mann DM, Behling CA, Konopka RG, Chiles PG, Pedersen CA, Moser KM. Percutaneous pulmonary endoarterial biopsy in an experimental model of pulmonary hypertension. Chest. 1998; 114: 241–250.CrossrefMedlineGoogle Scholar26 Kietselaer BL, Reutelingsperger CP, Heidendal GA, Daemen MJ, Mess WH, Hofstra L, Narula J. Noninvasive detection of plaque instability with use of radiolabeled annexin A5 in patients with carotid-artery atherosclerosis. N Engl J Med. 2004; 350: 1472–1473.CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited ByCulley M and Chan S (2022) Endothelial Senescence: A New Age in Pulmonary Hypertension, Circulation Research, 130:6, (928-941), Online publication date: 18-Mar-2022.Boucherat O, Agrawal V, Lawrie A and Bonnet S (2022) The Latest in Animal Models of Pulmonary Hypertension and Right Ventricular Failure, Circulation Research, 130:9, (1466-1486), Online publication date: 29-Apr-2022. Rajagopal S and Yu Y (2022) The Pathobiology of Pulmonary Arterial Hypertension, Cardiology Clinics, 10.1016/j.ccl.2021.08.001, 40:1, (1-12), Online publication date: 1-Feb-2022. Florentin J, Zhao J, Tai Y, Sun W, Ohayon L, O'Neil S, Arunkumar A, Zhang X, Zhu J, Al Aaraj Y, Watson A, Sembrat J, Rojas M, Chan S and Dutta P (2022) Loss of Amphiregulin drives inflammation and endothelial apoptosis in pulmonary hypertension, Life Science Alliance, 10.26508/lsa.202101264, 5:11, (e202101264), Online publication date: 1-Nov-2022. Awada C, Grobs Y, Wu W, Habbout K, Romanet C, Breuils-Bonnet S, Tremblay E, Martineau S, Paulin R, Bonnet S, Provencher S, Potus F and Boucherat O (2021) R-Crizotinib predisposes to and exacerbates pulmonary arterial hypertension in animal models, European Respiratory Journal, 10.1183/13993003.03271-2020, 57:5, (2003271), Online publication date: 1-May-2021. Negi V, Yang J, Speyer G, Pulgarin A, Handen A, Zhao J, Tai Y, Tang Y, Culley M, Yu Q, Forsythe P, Gorelova A, Watson A, Al Aaraj Y, Satoh T, Sharifi-Sanjani M, Rajaratnam A, Sembrat J, Provencher S, Yin X, Vargas S, Rojas M, Bonnet S, Torrino S, Wagner B, Schreiber S, Dai M, Bertero T, Al Ghouleh I, Kim S and Chan S (2021) Computational repurposing of therapeutic small molecules from cancer to pulmonary hypertension, Science Advances, 10.1126/sciadv.abh3794, 7:43, Online publication date: 22-Oct-2021. Vitry G, Paulin R, Grobs Y, Lampron M, Shimauchi T, Lemay S, Tremblay E, Habbout K, Awada C, Bourgeois A, Nadeau V, Paradis R, Breuils-Bonnet S, Roux-Dalvai F, Orcholski M, Potus F, Provencher S, Boucherat O and Bonnet S (2021) Oxidized DNA Precursors Cleanup by NUDT1 Contributes to Vascular Remodeling in Pulmonary Arterial Hypertension, American Journal of Respiratory and Critical Care Medicine, 10.1164/rccm.202003-0627OC, 203:5, (614-627), Online publication date: 1-Mar-2021. Gil-Ramírez A, Rosmark O, Spégel P, Swärd K, Westergren-Thorsson G, Larsson-Callerfelt A and Rodríguez-Meizoso I (2020) Pressurized carbon dioxide as a potential tool for decellularization of pulmonary arteries for transplant purposes, Scientific Reports, 10.1038/s41598-020-60827-4, 10:1, Online publication date: 1-Dec-2020. Yu Q, Tai Y, Tang Y, Zhao J, Negi V, Culley M, Pilli J, Sun W, Brugger K, Mayr J, Saggar R, Saggar R, Wallace W, Ross D, Waxman A, Wendell S, Mullett S, Sembrat J, Rojas M, Khan O, Dahlman J, Sugahara M, Kagiyama N, Satoh T, Zhang M, Feng N, Gorcsan J, Vargas S, Haley K, Kumar R, Graham B, Langer R, Anderson D, Wang B, Shiva S, Bertero T and Chan S (2019) BOLA (BolA Family Member 3) Deficiency Controls Endothelial Metabolism and Glycine Homeostasis in Pulmonary Hypertension, Circulation, 139:19, (2238-2255), Online publication date: 7-May-2019.Li B, He W, Ye L, Zhu Y, Tian Y, Chen L, Yang J, Miao M, Shi Y, Azevedo H, Ma Z and Hao K (2019) Targeted Delivery of Sildenafil for Inhibiting Pulmonary Vascular Remodeling, Hypertension, 73:3, (703-711), Online publication date: 1-Mar-2019. Farkas D, Thompson A, Bhagwani A, Hultman S, Ji H, Kotha N, Farr G, Arnold N, Braithwaite A, Casbolt H, Cole J, Sabroe I, Monaco C, Cool C, Goncharova E, Lawrie A and Farkas L (2019) Toll-like Receptor 3 Is a Therapeutic Target for Pulmonary Hypertension, American Journal of Respiratory and Critical Care Medicine, 10.1164/rccm.201707-1370OC, 199:2, (199-210), Online publication date: 15-Jan-2019. Harvey L and Chan S (2018) Evolving systems biology approaches to understanding non‐coding RNAs in pulmonary hypertension, The Journal of Physiology, 10.1113/JP275855, 597:4, (1199-1208), Online publication date: 1-Feb-2019. Arwood M, Vahabi N, Lteif C, Sharma R, Machado R and Duarte J (2019) Transcriptome-wide analysis associates ID2 expression with combined pre- and post-capillary pulmonary hypertension, Scientific Reports, 10.1038/s41598-019-55700-y, 9:1, Online publication date: 1-Dec-2019. Ranchoux B, Harvey L, Ayon R, Babicheva A, Bonnet S, Chan S, Yuan J and Perez V (2018) Endothelial dysfunction in pulmonary arterial hypertension: an evolving landscape (2017 Grover Conference Series), Pulmonary Circulation, 10.1177/2045893217752912, 8:1, (1-17), Online publication date: 1-Jan-2018. Kuebler W, Nicolls M, Olschewski A, Abe K, Rabinovitch M, Stewart D, Chan S, Morrell N, Archer S and Spiekerkoetter E (2018) A pro-con debate: current controversies in PAH pathogenesis at the American Thoracic Society International Conference in 2017, American Journal of Physiology-Lung Cellular and Molecular Physiology, 10.1152/ajplung.00150.2018, 315:4, (L502-L516), Online publication date: 1-Oct-2018. Michelakis E (2017) PVDOMICS Drive the Pulmonary Hypertension Field Into the Precision Medicine Era, Circulation Research, 121:10, (1106-1108), Online publication date: 27-Oct-2017. Bertero T, Rezzonico R, Pottier N and Mari B (2017) Impact of MicroRNAs in the Cellular Response to Hypoxia MiRNAs in Differentiation and Development, 10.1016/bs.ircmb.2017.03.006, (91-158), . Yu Q and Chan S (2017) Mitochondrial and Metabolic Drivers of Pulmonary Vascular Endothelial Dysfunction in Pulmonary Hypertension Pulmonary Vasculature Redox Signaling in Health and Disease, 10.1007/978-3-319-63245-2_24, (373-383), . Gurtu V and Michelakis E (2016) A Paradigm Shift Is Needed in the Field of Pulmonary Arterial Hypertension for Its Entrance Into the Precision Medicine Era, Circulation Research, 119:12, (1276-1279), Online publication date: 9-Dec-2016. Bertero T, Oldham W, Cottrill K, Pisano S, Vanderpool R, Yu Q, Zhao J, Tai Y, Tang Y, Zhang Y, Rehman S, Sugahara M, Qi Z, Gorcsan J, Vargas S, Saggar R, Saggar R, Wallace W, Ross D, Haley K, Waxman A, Parikh V, De Marco T, Hsue P, Morris A, Simon M, Norris K, Gaggioli C, Loscalzo J, Fessel J and Chan S (2016)(2016)(2016)(2016) Vascular stiffness mechanoactivates YAP/TAZ-dependent glutaminolysis to drive pulmonary hypertension, Journal of Clinical Investigation, 10.1172/JCI86387, 126:9, (3313-3335), Online publication date: 22-Aug-2016., Online publication date: 22-Aug-2016., Online publication date: 1-Sep-2016., Online publication date: 1-Sep-2016. Paulin R and Michelakis E (2014) The Metabolic Theory of Pulmonary Arterial Hypertension, Circulation Research, 115:1, (148-164), Online publication date: 20-Jun-2014.Mojiri A, Nakhaii-Nejad M, Phan W, Kulak S, Radziwon-Balicka A, Jurasz P, Michelakis E and Jahroudi N (2013) Hypoxia Results in Upregulation and De Novo Activation of Von Willebrand Factor Expression in Lung Endothelial Cells, Arteriosclerosis, Thrombosis, and Vascular Biology, 33:6, (1329-1338), Online publication date: 1-Jun-2013. Rothman A, Davidson S, Wiencek R, Evans W, Restrepo H, Sarukhanov V, Ruoslahti E, Williams R and Mann D (2013) Vascular Histomolecular Analysis by Sequential Endoarterial Biopsy in a Shunt Model of Pulmonary Hypertension, Pulmonary Circulation, 10.4103/2045-8932.109913, 3:1, (50-57), Online publication date: 1-Jan-2013. Dromparis P and Michelakis E (2013) Mitochondria in Vascular Health and Disease, Annual Review of Physiology, 10.1146/annurev-physiol-030212-183804, 75:1, (95-126), Online publication date: 10-Feb-2013. Akagi S, Nakamura K, Matsubara H, Fukushima Kusano K, Kataoka N, Oto T, Miyaji K, Miura A, Ogawa A, Yoshida M, Ueda-Ishibashi H, Yutani C and Ito H (2013) Prostaglandin I2 induces apoptosis via upregulation of Fas ligand in pulmonary artery smooth muscle cells from patients with idiopathic pulmonary arterial hypertension, International Journal of Cardiology, 10.1016/j.ijcard.2011.09.004, 165:3, (499-505), Online publication date: 1-May-2013. Bogaard H, Mizuno S, Guignabert C, Al Hussaini A, Farkas D, Ruiter G, Kraskauskas D, Fadel E, Allegood J, Humbert M, Noordegraaf A, Spiegel S, Farkas L and Voelkel N (2012) Copper Dependence of Angioproliferation in Pulmonary Arterial Hypertension in Rats and Humans, American Journal of Respiratory Cell and Molecular Biology, 10.1165/rcmb.2011-0296OC, 46:5, (582-591), Online publication date: 1-May-2012. Gelosa P, Sevin G, Pignieri A, Budelli S, Castiglioni L, Blanc-Guillemaud V, Lerond L, Tremoli E and Sironi L (2011) Terutroban, a thromboxane/prostaglandin endoperoxide receptor antagonist, prevents hypertensive vascular hypertrophy and fibrosis, American Journal of Physiology-Heart and Circulatory Physiology, 10.1152/ajpheart.00880.2010, 300:3, (H762-H768), Online publication date: 1-Mar-2011. Dromparis P, Sutendra G and Michelakis E (2010) The role of mitochondria in pulmonary vascular remodeling, Journal of Molecular Medicine, 10.1007/s00109-010-0670-x, 88:10, (1003-1010), Online publication date: 1-Oct-2010. Gomberg-Maitland M, Maitland M, Barst R, Sugeng L, Coslet S, Perrino T, Bond L, LaCouture M, Archer S and Ratain M (2009) A Dosing/Cross-Development Study of the Multikinase Inhibitor Sorafenib in Patients With Pulmonary Arterial Hypertension, Clinical Pharmacology & Therapeutics, 10.1038/clpt.2009.217, 87:3, (303-310), Online publication date: 1-Mar-2010. Chandra S, Shah S, Thenappan T, Archer S, Rich S and Gomberg-Maitland M (2010) Carbon monoxide diffusing capacity and mortality in pulmonary arterial hypertension, The Journal of Heart and Lung Transplantation, 10.1016/j.healun.2009.07.005, 29:2, (181-187), Online publication date: 1-Feb-2010. Yildiz P (2009) Molecular mechanisms of pulmonary hypertension, Clinica Chimica Acta, 10.1016/j.cca.2009.01.018, 403:1-2, (9-16), Online publication date: 1-May-2009. Langleben D (2009) Near-Term Novel Therapies for PAH, Advances in Pulmonary Hypertension, 10.21693/1933-088X-8.1.17, 8:1, (17-20), Online publication date: 1-Jan-2009. Archer S and Michelakis E (2009) Phosphodiesterase Type 5 Inhibitors for Pulmonary Arterial Hypertension, New England Journal of Medicine, 10.1056/NEJMct0904473, 361:19, (1864-1871), Online publication date: 5-Nov-2009. Homma N, Nagaoka T, Karoor V, Imamura M, Taraseviciene-Stewart L, Walker L, Fagan K, McMurtry I and Oka M (2008) Involvement of RhoA/Rho kinase signaling in protection against monocrotaline-induced pulmonary hypertension in pneumonectomized rats by dehydroepiandrosterone, American Journal of Physiology-Lung Cellular and Molecular Physiology, 10.1152/ajplung.90251.2008, 295:1, (L71-L78), Online publication date: 1-Jul-2008. Desai R, Torres F and Gupta H (2008) Role of Cardiac MRI in Pulmonary Hypertension, Advances in Pulmonary Hypertension, 10.21693/1933-088X-7.4.396, 7:4, (396-402), Online publication date: 1-Dec-2008. Sutendra G and Michelakis E (2008) Chapter 5 A Mitochondria-AOS-Kv Channel Axis in Health and Disease; New Insights and Therapeutic Targets for Vascular Disease and Cancer Free Radical Effects on Membranes, 10.1016/S1063-5823(08)00205-6, (87-112), . Timens W (2008) Pulmonary Arterial Hypertension Molecular Pathology of Lung Diseases, 10.1007/978-0-387-72430-0_58, (634-643), . Lee M and Griendling K (2008) Redox Signaling, Vascular Function, and Hypertension, Antioxidants & Redox Signaling, 10.1089/ars.2007.1986, 10:6, (1045-1059), Online publication date: 1-Jun-2008. Aird W (2007) Phenotypic Heterogeneity of the Endothelium, Circulation Research, 100:2, (174-190), Online publication date: 2-Feb-2007. McMurtry M, Bonnet S, Michelakis E, Bonnet S, Haromy A and Archer S (2007) Statin therapy, alone or with rapamycin, does not reverse monocrotaline pulmonary arterial hypertension: the rapamcyin-atorvastatin-simvastatin study, American Journal of Physiology-Lung Cellular and Molecular Physiology, 10.1152/ajplung.00310.2006, 293:4, (L933-L940), Online publication date: 1-Oct-2007. Ali O, Wharton J, Gibbs J, Howard L and Wilkins M (2007) Emerging therapies for pulmonary arterial hypertension, Expert Opinion on Investigational Drugs, 10.1517/13543784.16.6.803, 16:6, (803-818), Online publication date: 1-Jun-2007. Bonnet S, Rochefort G, Sutendra G, Archer S, Haromy A, Webster L, Hashimoto K, Bonnet S and Michelakis E (2007) The nuclear factor of activated T cells in pulmonary arterial hypertension can be therapeutically targeted, Proceedings of the National Academy of Sciences, 10.1073/pnas.0610467104, 104:27, (11418-11423), Online publication date: 3-Jul-2007. McMurtry M, Moudgil R, Hashimoto K, Bonnet S, Michelakis E and Archer S (2007) Overexpression of human bone morphogenetic protein receptor 2 does not ameliorate monocrotaline pulmonary arterial hypertension, American Journal of Physiology-Lung Cellular and Molecular Physiology, 10.1152/ajplung.00309.2006, 292:4, (L872-L878), Online publication date: 1-Apr-2007. Langleben D (2007) Endothelin Receptor Antagonists in the Treatment of Pulmonary Arterial Hypertension, Clinics in Chest Medicine, 10.1016/j.ccm.2006.11.002, 28:1, (117-125), Online publication date: 1-Mar-2007. Sehgal P, Mukhopadhyay S, Xu F, Patel K and Shah M (2007) Dysfunction of Golgi tethers, SNAREs, and SNAPs in monocrotaline-induced pulmonary hypertension, American Journal of Physiology-Lung Cellular and Molecular Physiology, 10.1152/ajplung.00463.2006, 292:6, (L1526-L1542), Online publication date: 1-Jun-2007. Robitaille G, Hénault J, Christin M, Senécal J and Raymond Y (2007) The nuclear autoantigen CENP-B displays cytokine-like activities toward vascular smooth muscle cells, Arthritis & Rheumatism, 10.1002/art.22972, 56:11, (3814-3826), Online publication date: 1-Nov-2007. Nagendran J and Michelakis E (2007) MRI, Chest, 10.1378/chest.07-0563, 132:1, (2-5), Online publication date: 1-Jul-2007. Adnot S and Eddahibi S (2007) Lessons from oncology to understand and treat pulmonary hypertension, International Journal of Clinical Practice, 10.1111/j.1742-1241.2007.01618.x, 61, (19-25) Archer S and Michelakis E (2006) An evidence-based approach to the management of pulmonary arterial hypertension, Current Opinion in Cardiology, 10.1097/01.hco.0000231410.07426.9b, 21:4, (385-392), Online publication date: 1-Jul-2006. Deng L, Han X, Wang Z, Nie X and Bian J (2022) The Landscape of Noncoding RNA in Pulmonary Hypertension, Biomolecules, 10.3390/biom12060796, 12:6, (796) Bertero T, Handen A and Chan S (2018) Factors Associated with Heritable Pulmonary Arterial Hypertension Exert Convergent Actions on the miR-130/301-Vascular Matrix Feedback Loop, International Journal of Molecular Sciences, 10.3390/ijms19082289, 19:8, (2289) Suen C, Mei S, Kugathasan L and Stewart D (2013) Targeted Delivery of Genes to Endothelial Cells and Cell‐ and Gene‐Based Therapy in Pulmonary Vascular Diseases Comprehensive Physiology, 10.1002/cphy.c120034, (1749-1779) February 3, 2006Vol 98, Issue 2 Advertisement Article InformationMetrics https://doi.org/10.1161/01.RES.0000204572.65400.a5PMID: 16456109 Originally publishedFebruary 3, 2006 Keywordsapoptosispulmonary circulationsurvivinpulmonary hypertensionvascular remodelingPDF download Advertisement
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