Aberrant Pulmonary Vascular Growth and Remodeling in Bronchopulmonary Dysplasia

Cristina M Alvira, Cristina M Alvira

Abstract

In contrast to many other organs, a significant portion of lung development occurs after birth during alveolarization, thus rendering the lung highly susceptible to injuries that may disrupt this developmental process. Premature birth heightens this susceptibility, with many premature infants developing the chronic lung disease, bronchopulmonary dysplasia (BPD), a disease characterized by arrested alveolarization. Over the past decade, tremendous progress has been made in the elucidation of mechanisms that promote postnatal lung development, including extensive data suggesting that impaired pulmonary angiogenesis contributes to the pathogenesis of BPD. Moreover, in addition to impaired vascular growth, patients with BPD also frequently demonstrate alterations in pulmonary vascular remodeling and tone, increasing the risk for persistent hypoxemia and the development of pulmonary hypertension. In this review, an overview of normal lung development will be presented, and the pathologic features of arrested development observed in BPD will be described, with a specific emphasis on the pulmonary vascular abnormalities. Key pathways that promote normal pulmonary vascular development will be reviewed, and the experimental and clinical evidence demonstrating alterations of these essential pathways in BPD summarized.

Keywords: HIF; VEGF; alveolarization; chronic lung disease; nitric oxide; pulmonary angiogenesis; pulmonary hypertension.

Figures

Figure 1
Figure 1
The interplay of pathologic and clinical factors that lead to pulmonary hypertension in bronchopulmonary dysplasia. Dysmorphic vascular development as a result of altered angiogenic signaling combines with impairments in secondary septation, leading to the development of BPD. These events set the stage, pre- and postnatally, for the development of pulmonary hypertension. The decrease in gas exchange surface area resulting from the impaired secondary septation also sets up a vicious cycle of hypoxemia and dead space ventilation that prolongs the need for mechanical ventilation and oxygen therapy, and induces pathologic changes in pulmonary vascular remodeling and tone, further increasing the risk of pulmonary hypertension.

References

    1. Galambos C, Demello DE. Regulation of alveologenesis: clinical implications of impaired growth. Pathology (2008) 40(2):124–40.10.1080/00313020701818981
    1. Jobe AH, Bancalari E. Bronchopulmonary dysplasia. Am J Respir Crit Care Med (2001) 163(7):1723–9.10.1164/ajrccm.163.7.2011060
    1. Kinsella JP, Greenough A, Abman SH. Bronchopulmonary dysplasia. Lancet (2006) 367(9520):1421–31.10.1016/S0140-6736(06)68615-7
    1. Northway WH, Jr, Rosan RC, Porter DY. Pulmonary disease following respirator therapy of hyaline-membrane disease. Bronchopulmonary dysplasia. N Engl J Med (1967) 276(7):357–68.10.1056/NEJM196702162760701
    1. Jobe AJ. The new BPD: an arrest of lung development. Pediatr Res (1999) 46(6):641–3.10.1203/00006450-199912000-00007
    1. Bhatt AJ, Pryhuber GS, Huyck H, Watkins RH, Metlay LA, Maniscalco WM. Disrupted pulmonary vasculature and decreased vascular endothelial growth factor, Flt-1, and TIE-2 in human infants dying with bronchopulmonary dysplasia. Am J Respir Crit Care Med (2001) 164(10 Pt 1):1971–80.10.1164/ajrccm.164.10.2101140
    1. Thébaud B, Ladha F, Michelakis ED, Sawicka M, Thurston G, Eaton F, et al. Vascular endothelial growth factor gene therapy increases survival, promotes lung angiogenesis, and prevents alveolar damage in hyperoxia-induced lung injury: evidence that angiogenesis participates in alveolarization. Circulation (2005) 112(16):2477–86.10.1161/CIRCULATIONAHA.105.541524
    1. Jakkula M, Le Cras TD, Gebb S, Hirth KP, Tuder RM, Voelkel NF, et al. Inhibition of angiogenesis decreases alveolarization in the developing rat lung. Am J Physiol Lung Cell Mol Physiol (2000) 279(3):L600–7.
    1. Le Cras TD, Markham NE, Tuder RM, Voelkel NF, Abman SH. Treatment of newborn rats with a VEGF receptor inhibitor causes pulmonary hypertension and abnormal lung structure. Am J Physiol Lung Cell Mol Physiol (2002) 283(3):L555–62.10.1152/ajplung.00408.2001
    1. Hislop AA. Airway and blood vessel interaction during lung development. J Anat (2002) 201(4):325–34.10.1046/j.1469-7580.2002.00097.x
    1. Hislop A. Developmental biology of the pulmonary circulation. Paediatr Respir Rev (2005) 6(1):35–43.10.1016/j.prrv.2004.11.009
    1. Ochs M, Nyengaard JR, Jung A, Knudsen L, Voigt M, Wahlers T, et al. The number of alveoli in the human lung. Am J Respir Crit Care Med (2004) 169(1):120–4.10.1164/rccm.200308-1107OC
    1. Hislop AA, Pierce CM. Growth of the vascular tree. Paediatr Respir Rev (2000) 1(4):321–7.10.1053/prrv.2000.0071
    1. Flamme I, Risau W. Induction of vasculogenesis and hematopoiesis in vitro. Development (1992) 116(2):435–9.
    1. Risau W. Mechanisms of angiogenesis. Nature (1997) 386(6626):671–4.10.1038/386671a0
    1. deMello DE, Sawyer D, Galvin N, Reid LM. Early fetal development of lung vasculature. Am J Respir Cell Mol Biol (1997) 16(5):568–81.10.1165/ajrcmb.16.5.9160839
    1. Schachtner SK, Wang Y, Scott Baldwin H. Qualitative and quantitative analysis of embryonic pulmonary vessel formation. Am J Respir Cell Mol Biol (2000) 22(2):157–65.10.1165/ajrcmb.22.2.3766
    1. Stenmark KR, Abman SH. Lung vascular development: implications for the pathogenesis of bronchopulmonary dysplasia. Annu Rev Physiol (2005) 67:623–61.10.1146/annurev.physiol.67.040403.102229
    1. Chambers HM, van Velzen D. Ventilator-related pathology in the extremely immature lung. Pathology (1989) 21(2):79–83.10.3109/00313028909059539
    1. Hislop AA, Haworth SG. Pulmonary vascular damage and the development of cor pulmonale following hyaline membrane disease. Pediatr Pulmonol (1990) 9(3):152–61.10.1002/ppul.1950090306
    1. Gorenflo M, Vogel M, Obladen M. Pulmonary vascular changes in bronchopulmonary dysplasia: a clinicopathologic correlation in short- and long-term survivors. Pediatr Pathol (1991) 11(6):851–66.10.3109/15513819109065482
    1. Margraf LR, Tomashefski JF, Jr, Bruce MC, Dahms BB. Morphometric analysis of the lung in bronchopulmonary dysplasia. Am Rev Respir Dis (1991) 143(2):391–400.10.1164/ajrccm/143.2.391
    1. Husain AN, Siddiqui NH, Stocker JT. Pathology of arrested acinar development in postsurfactant bronchopulmonary dysplasia. Hum Pathol (1998) 29(7):710–7.10.1016/S0046-8177(98)90280-5
    1. O’Brodovich HM, Mellins RB. Bronchopulmonary dysplasia. Unresolved neonatal acute lung injury. Am Rev Respir Dis (1985) 132(3):694–709.
    1. Coalson JJ. Chronic Lung Disease in Early Infancy. New York: Marcel Dekker; (2000).
    1. Bush A, Busst CM, Knight WB, Hislop AA, Haworth SG, Shinebourne EA. Changes in pulmonary circulation in severe bronchopulmonary dysplasia. Arch Dis Child (1990) 65(7):739–45.10.1136/adc.65.7.739
    1. De Paepe ME, Mao Q, Powell J, Rubin SE, DeKoninck P, Appel N, et al. Growth of pulmonary microvasculature in ventilated preterm infants. Am J Respir Crit Care Med (2006) 173(2):204–11.10.1164/rccm.200506-927OC
    1. Fouron JC, Le Guennec JC, Villemant D, Perreault G, Davignon A. Value of echocardiography in assessing the outcome of bronchopulmonary dysplasia of the newborn. Pediatrics (1980) 65(3):529–35.
    1. Berman W, Jr, Katz R, Yabek SM, Dillon T, Fripp RR, Papile LA. Long-term follow-up of bronchopulmonary dysplasia. J Pediatr (1986) 109(1):45–50.10.1016/S0022-3476(86)80570-4
    1. Slaughter JL, Pakrashi T, Jones DE, South AP, Shah TA. Echocardiographic detection of pulmonary hypertension in extremely low birth weight infants with bronchopulmonary dysplasia requiring prolonged positive pressure ventilation. J Perinatol (2011) 31(10):635–40.10.1038/jp.2010.213
    1. Mourani PM, Sontag MK, Younoszai A, Miller JI, Kinsella JP, Baker CD, et al. Early pulmonary vascular disease in preterm infants at risk for bronchopulmonary dysplasia. Am J Respir Crit Care Med (2015) 191(1):87–95.10.1164/rccm.201409-1594OC
    1. Kim DH, Kim HS, Choi CW, Kim EK, Kim BI, Choi JH. Risk factors for pulmonary artery hypertension in preterm infants with moderate or severe bronchopulmonary dysplasia. Neonatology (2012) 101(1):40–6.10.1159/000327891
    1. Khemani E, McElhinney DB, Rhein L, Andrade O, Lacro RV, Thomas KC, et al. Pulmonary artery hypertension in formerly premature infants with bronchopulmonary dysplasia: clinical features and outcomes in the surfactant era. Pediatrics (2007) 120(6):1260–9.10.1542/peds.2007-0971
    1. Kumar VH, Hutchison AA, Lakshminrusimha S, Morin FC, III, Wynn RJ, Ryan RM. Characteristics of pulmonary hypertension in preterm neonates. J Perinatol (2007) 27(4):214–9.10.1038/sj.jp.7211673
    1. Mirza H, Ziegler J, Ford S, Padbury J, Tucker R, Laptook A. Pulmonary hypertension in preterm infants: prevalence and association with bronchopulmonary dysplasia. J Pediatr (2014) 165(5):909.e–14.e.10.1016/j.jpeds.2014.07.040
    1. Tomashefski JF, Jr, Oppermann HC, Vawter GF, Reid LM. Bronchopulmonary dysplasia: a morphometric study with emphasis on the pulmonary vasculature. Pediatr Pathol (1984) 2(4):469–87.10.3109/15513818409025895
    1. Thibeault DW, Truog WE, Ekekezie II. Acinar arterial changes with chronic lung disease of prematurity in the surfactant era. Pediatr Pulmonol (2003) 36(6):482–9.10.1002/ppul.10349
    1. Parker TA, Abman SH. The pulmonary circulation in bronchopulmonary dysplasia. Semin Neonatol (2003) 8(1):51–61.10.1016/S1084-2756(02)00191-4
    1. Abman SH, Wolfe RR, Accurso FJ, Koops BL, Bowman CM, Wiggins JW, Jr. Pulmonary vascular response to oxygen in infants with severe bronchopulmonary dysplasia. Pediatrics (1985) 75(1):80–4.
    1. Goodman G, Perkin RM, Anas NG, Sperling DR, Hicks DA, Rowen M. Pulmonary hypertension in infants with bronchopulmonary dysplasia. J Pediatr (1988) 112(1):67–72.10.1016/S0022-3476(88)80125-2
    1. Mourani PM, Ivy DD, Gao D, Abman SH. Pulmonary vascular effects of inhaled nitric oxide and oxygen tension in bronchopulmonary dysplasia. Am J Respir Crit Care Med (2004) 170(9):1006–13.10.1164/rccm.200310-1483OC
    1. Ascher DP, Rosen P, Null DM, de Lemos RA, Wheller JJ. Systemic to pulmonary collaterals mimicking patent ductus arteriosus in neonates with prolonged ventilatory courses. J Pediatr (1985) 107(2):282–4.10.1016/S0022-3476(85)80150-5
    1. Covert RF, Drummond WH, Gessner IH. Collateral vessels complicating bronchopulmonary dysplasia. J Pediatr (1988) 113(3):617–8.10.1016/S0022-3476(88)80672-3
    1. Galambos C, Sims-Lucas S, Abman SH. Histologic evidence of intrapulmonary anastomoses by three-dimensional reconstruction in severe bronchopulmonary dysplasia. Ann Am Thorac Soc (2013) 10(5):474–81.10.1513/AnnalsATS.201305-124OC
    1. Acker SN, Mandell EW, Sims-Lucas S, Gien J, Abman SH, Galambos C. Histologic identification of prominent intrapulmonary anastomotic vessels in severe congenital diaphragmatic hernia. J Pediatr (2015) 166(1):178–83.10.1016/j.jpeds.2014.09.010
    1. Ali N, Abman SH, Galambos C. Histologic evidence of intrapulmonary bronchopulmonary anastomotic pathways in neonates with meconium aspiration syndrome. J Pediatr (2015) 167:1445–7.10.1016/j.jpeds.2015.08.049
    1. Ng YS, Rohan R, Sunday ME, Demello DE, D’Amore PA. Differential expression of VEGF isoforms in mouse during development and in the adult. Dev Dyn (2001) 220(2):112–21.10.1002/1097-0177(2000)9999:9999<::AID-DVDY1093>;2-D
    1. Hara A, Chapin CJ, Ertsey R, Kitterman JA. Changes in fetal lung distension alter expression of vascular endothelial growth factor and its isoforms in developing rat lung. Pediatr Res (2005) 58(1):30–7.10.1203/01.PDR.0000163614.20031.C5
    1. Kaipainen A, Korhonen J, Pajusola K, Aprelikova O, Persico MG, Terman BI, et al. The related FLT4, FLT1, and KDR receptor tyrosine kinases show distinct expression patterns in human fetal endothelial cells. J Exp Med (1993) 178(6):2077–88.10.1084/jem.178.6.2077
    1. Kendall RL, Thomas KA. Inhibition of vascular endothelial cell growth factor activity by an endogenously encoded soluble receptor. Proc Natl Acad Sci U S A (1993) 90(22):10705–9.10.1073/pnas.90.22.10705
    1. Roda JM, Sumner LA, Evans R, Phillips GS, Marsh CB, Eubank TD. Hypoxia-inducible factor-2alpha regulates GM-CSF-derived soluble vascular endothelial growth factor receptor 1 production from macrophages and inhibits tumor growth and angiogenesis. J Immunol (2011) 187(4):1970–6.10.4049/jimmunol.1100841
    1. Kendall RL, Wang G, Thomas KA. Identification of a natural soluble form of the vascular endothelial growth factor receptor, FLT-1, and its heterodimerization with KDR. Biochem Biophys Res Commun (1996) 226(2):324–8.10.1006/bbrc.1996.1355
    1. Shalaby F, Rossant J, Yamaguchi TP, Gertsenstein M, Wu XF, Breitman ML, et al. Failure of blood-island formation and vasculogenesis in Flk-1-deficient mice. Nature (1995) 376(6535):62–6.10.1038/376062a0
    1. Fong GH, Rossant J, Gertsenstein M, Breitman ML. Role of the Flt-1 receptor tyrosine kinase in regulating the assembly of vascular endothelium. Nature (1995) 376(6535):66–70.10.1038/376066a0
    1. Carmeliet P, Ferreira V, Breier G, Pollefeyt S, Kieckens L, Gertsenstein M, et al. Abnormal blood vessel development and lethality in embryos lacking a single VEGF allele. Nature (1996) 380(6573):435–9.10.1038/380435a0
    1. Ferrara N, Carver-Moore K, Chen H, Dowd M, Lu L, O’Shea KS, et al. Heterozygous embryonic lethality induced by targeted inactivation of the VEGF gene. Nature (1996) 380(6573):439–42.10.1038/380439a0
    1. Galambos C, Ng YS, Ali A, Noguchi A, Lovejoy S, D’Amore PA, et al. Defective pulmonary development in the absence of heparin-binding vascular endothelial growth factor isoforms. Am J Respir Cell Mol Biol (2002) 27(2):194–203.10.1165/ajrcmb.27.2.4703
    1. Gerber HP, Hillan KJ, Ryan AM, Kowalski J, Keller GA, Rangell L, et al. VEGF is required for growth and survival in neonatal mice. Development (1999) 126(6):1149–59.
    1. Zeng X, Wert SE, Federici R, Peters KG, Whitsett JA. VEGF enhances pulmonary vasculogenesis and disrupts lung morphogenesis in vivo. Dev Dyn (1998) 211(3):215–27.10.1002/(SICI)1097-0177(199803)211:3<215::AID-AJA3>;2-K
    1. Maniscalco WM, Watkins RH, D’Angio CT, Ryan RM. Hyperoxic injury decreases alveolar epithelial cell expression of vascular endothelial growth factor (VEGF) in neonatal rabbit lung. Am J Respir Cell Mol Biol (1997) 16(5):557–67.10.1165/ajrcmb.16.5.9160838
    1. Perkett EA, Klekamp JG. Vascular endothelial growth factor expression is decreased in rat lung following exposure to 24 or 48 hours of hyperoxia: implications for endothelial cell survival. Chest (1998) 114(1 Suppl):52S–3S.10.1378/chest.114.1_Supplement.52S
    1. Hosford GE, Olson DM. Effects of hyperoxia on VEGF, its receptors, and HIF-2alpha in the newborn rat lung. Am J Physiol Lung Cell Mol Physiol (2003) 285(1):L161–8.10.1152/ajplung.00285.2002
    1. Maniscalco WM, Watkins RH, Pryhuber GS, Bhatt A, Shea C, Huyck H. Angiogenic factors and alveolar vasculature: development and alterations by injury in very premature baboons. Am J Physiol Lung Cell Mol Physiol (2002) 282(4):L811–23.10.1152/ajplung.00325.2001
    1. Bland RD, Mokres LM, Ertsey R, Jacobson BE, Jiang S, Rabinovitch M, et al. Mechanical ventilation with 40% oxygen reduces pulmonary expression of genes that regulate lung development and impairs alveolar septation in newborn mice. Am J Physiol Lung Cell Mol Physiol (2007) 293(5):L1099–110.10.1152/ajplung.00217.2007
    1. Iosef C, Alastalo TP, Hou Y, Chen C, Adams ES, Lyu SC, et al. Inhibiting NF-kappaB in the developing lung disrupts angiogenesis and alveolarization. Am J Physiol Lung Cell Mol Physiol (2012) 302(10):L1023–36.10.1152/ajplung.00230.2011
    1. Hou Y, Liu M, Husted C, Chen C, Thiagarajan K, Johns JL, et al. Activation of the nuclear factor-kappaB pathway during postnatal lung inflammation preserves alveolarization by suppressing macrophage inflammatory protein-2. Am J Physiol Lung Cell Mol Physiol (2015) 309(6):L593–604.10.1152/ajplung.00029.2015
    1. Thebaud B, Ladha F, Michelakis ED, Sawicka M, Thurston G, Eaton F, et al. Vascular endothelial growth factor gene therapy increases survival, promotes lung angiogenesis, and prevents alveolar damage in hyperoxia-induced lung injury: evidence that angiogenesis participates in alveolarization. Circulation (2005) 112(16):2477–86.10.1161/CIRCULATIONAHA.105.541524
    1. Groenman F, Rutter M, Caniggia I, Tibboel D, Post M. Hypoxia-inducible factors in the first trimester human lung. J Histochem Cytochem (2007) 55(4):355–63.10.1369/jhc.6A7129.2006
    1. Asikainen TM, Ahmad A, Schneider BK, White CW. Effect of preterm birth on hypoxia-inducible factors and vascular endothelial growth factor in primate lungs. Pediatr Pulmonol (2005) 40(6):538–46.10.1002/ppul.20321
    1. Ema M, Taya S, Yokotani N, Sogawa K, Matsuda Y, Fujii-Kuriyama Y. A novel bHLH-PAS factor with close sequence similarity to hypoxia-inducible factor 1alpha regulates the VEGF expression and is potentially involved in lung and vascular development. Proc Natl Acad Sci U S A (1997) 94(9):4273–8.10.1073/pnas.94.9.4273
    1. Iyer NV, Kotch LE, Agani F, Leung SW, Laughner E, Wenger RH, et al. Cellular and developmental control of O2 homeostasis by hypoxia-inducible factor 1 alpha. Genes Dev (1998) 12(2):149–62.10.1101/gad.12.2.149
    1. Kotch LE, Iyer NV, Laughner E, Semenza GL. Defective vascularization of HIF-1alpha-null embryos is not associated with VEGF deficiency but with mesenchymal cell death. Dev Biol (1999) 209(2):254–67.10.1006/dbio.1999.9253
    1. Compernolle V, Brusselmans K, Acker T, Hoet P, Tjwa M, Beck H, et al. Loss of HIF-2alpha and inhibition of VEGF impair fetal lung maturation, whereas treatment with VEGF prevents fatal respiratory distress in premature mice. Nat Med (2002) 8(7):702–10.10.1038/nm1102-1329b
    1. Maltepe E, Schmidt JV, Baunoch D, Bradfield CA, Simon MC. Abnormal angiogenesis and responses to glucose and oxygen deprivation in mice lacking the protein ARNT. Nature (1997) 386(6623):403–7.10.1038/386403a0
    1. Grover TR, Asikainen TM, Kinsella JP, Abman SH, White CW. Hypoxia-inducible factors HIF-1alpha and HIF-2alpha are decreased in an experimental model of severe respiratory distress syndrome in preterm lambs. Am J Physiol Lung Cell Mol Physiol (2007) 292(6):L1345–51.10.1152/ajplung.00372.2006
    1. Truog WE, Xu D, Ekekezie II, Mabry S, Rezaiekhaligh M, Svojanovsky S, et al. Chronic hypoxia and rat lung development: analysis by morphometry and directed microarray. Pediatr Res (2008) 64(1):56–62.10.1203/PDR.0b013e31817289f2
    1. Asikainen TM, Schneider BK, Waleh NS, Clyman RI, Ho WB, Flippin LA, et al. Activation of hypoxia-inducible factors in hyperoxia through prolyl 4-hydroxylase blockade in cells and explants of primate lung. Proc Natl Acad Sci U S A (2005) 102(29):10212–7.10.1073/pnas.0504520102
    1. Asikainen TM, Waleh NS, Schneider BK, Clyman RI, White CW. Enhancement of angiogenic effectors through hypoxia-inducible factor in preterm primate lung in vivo. Am J Physiol Lung Cell Mol Physiol (2006) 291(4):L588–95.10.1152/ajplung.00098.2006
    1. Asikainen TM, Chang LY, Coalson JJ, Schneider BK, Waleh NS, Ikegami M, et al. Improved lung growth and function through hypoxia-inducible factor in primate chronic lung disease of prematurity. FASEB J (2006) 20(10):1698–700.10.1096/fj.06-5887fje
    1. Choi CW, Lee J, Lee HJ, Park HS, Chun YS, Kim BI. Deferoxamine improves alveolar and pulmonary vascular development by upregulating hypoxia-inducible factor-1alpha in a rat model of bronchopulmonary dysplasia. J Korean Med Sci (2015) 30(9):1295–301.10.3346/jkms.2015.30.9.1295
    1. Park HS, Park JW, Kim HJ, Choi CW, Lee HJ, Kim BI, et al. Sildenafil alleviates bronchopulmonary dysplasia in neonatal rats by activating the hypoxia-inducible factor signaling pathway. Am J Respir Cell Mol Biol (2013) 48(1):105–13.10.1165/rcmb.2012-0043OC
    1. Sessa WC. Molecular control of blood flow and angiogenesis: role of nitric oxide. J Thromb Haemost (2009) 7(Suppl 1):35–7.10.1111/j.1538-7836.2009.03424.x
    1. Mitchell JA, Ali F, Bailey L, Moreno L, Harrington LS. Role of nitric oxide and prostacyclin as vasoactive hormones released by the endothelium. Exp Physiol (2008) 93(1):141–7.10.1113/expphysiol.2007.038588
    1. Sase K, Michel T. Expression and regulation of endothelial nitric oxide synthase. Trends Cardiovasc Med (1997) 7(1):28–37.10.1016/S1050-1738(96)00121-1
    1. Arnal JF, Dinh-Xuan AT, Pueyo M, Darblade B, Rami J. Endothelium-derived nitric oxide and vascular physiology and pathology. Cell Mol Life Sci (1999) 55(8–9):1078–87.10.1007/s000180050358
    1. Kroll J, Waltenberger J. VEGF-A induces expression of eNOS and iNOS in endothelial cells via VEGF receptor-2 (KDR). Biochem Biophys Res Commun (1998) 252(3):743–6.10.1006/bbrc.1998.9719
    1. Shen BQ, Lee DY, Zioncheck TF. Vascular endothelial growth factor governs endothelial nitric-oxide synthase expression via a KDR/Flk-1 receptor and a protein kinase C signaling pathway. J Biol Chem (1999) 274(46):33057–63.10.1074/jbc.274.46.33057
    1. Fukumura D, Gohongi T, Kadambi A, Izumi Y, Ang J, Yun CO, et al. Predominant role of endothelial nitric oxide synthase in vascular endothelial growth factor-induced angiogenesis and vascular permeability. Proc Natl Acad Sci U S A (2001) 98(5):2604–9.10.1073/pnas.041359198
    1. Ziche M, Morbidelli L, Choudhuri R, Zhang HT, Donnini S, Granger HJ, et al. Nitric oxide synthase lies downstream from vascular endothelial growth factor-induced but not basic fibroblast growth factor-induced angiogenesis. J Clin Invest (1997) 99(11):2625–34.10.1172/JCI119451
    1. Murohara T, Asahara T, Silver M, Bauters C, Masuda H, Kalka C, et al. Nitric oxide synthase modulates angiogenesis in response to tissue ischemia. J Clin Invest (1998) 101(11):2567–78.10.1172/JCI1560
    1. Lee PC, Salyapongse AN, Bragdon GA, Shears LL, II, Watkins SC, Edington HD, et al. Impaired wound healing and angiogenesis in eNOS-deficient mice. Am J Physiol (1999) 277(4 Pt 2):H1600–8.
    1. Liao JK, Zulueta JJ, Yu FS, Peng HB, Cote CG, Hassoun PM. Regulation of bovine endothelial constitutive nitric oxide synthase by oxygen. J Clin Invest (1995) 96(6):2661–6.10.1172/JCI118332
    1. McQuillan LP, Leung GK, Marsden PA, Kostyk SK, Kourembanas S. Hypoxia inhibits expression of eNOS via transcriptional and posttranscriptional mechanisms. Am J Physiol (1994) 267(5 Pt 2):H1921–7.
    1. MacRitchie AN, Albertine KH, Sun J, Lei PS, Jensen SC, Freestone AA, et al. Reduced endothelial nitric oxide synthase in lungs of chronically ventilated preterm lambs. Am J Physiol Lung Cell Mol Physiol (2001) 281(4):L1011–20.
    1. Afshar S, Gibson LL, Yuhanna IS, Sherman TS, Kerecman JD, Grubb PH, et al. Pulmonary NO synthase expression is attenuated in a fetal baboon model of chronic lung disease. Am J Physiol Lung Cell Mol Physiol (2003) 284(5):L749–58.10.1152/ajplung.00334.2002
    1. Kallapur SG, Bachurski CJ, Le Cras TD, Joshi SN, Ikegami M, Jobe AH. Vascular changes after intra-amniotic endotoxin in preterm lamb lungs. Am J Physiol Lung Cell Mol Physiol (2004) 287(6):L1178–85.10.1152/ajplung.00049.2004
    1. Rozance PJ, Seedorf GJ, Brown A, Roe GB, O’Meara MC, Gien J, et al. Intrauterine growth restriction decreases pulmonary alveolar and vessel growth and causes pulmonary artery endothelial cell dysfunction in vitro in fetal sheep. Am J Physiol Lung Cell Mol Physiol (2011) 301:L860–71.10.1152/ajplung.00197.2011
    1. Leuwerke SM, Kaza AK, Tribble CG, Kron IL, Laubach VE. Inhibition of compensatory lung growth in endothelial nitric oxide synthase-deficient mice. Am J Physiol Lung Cell Mol Physiol (2002) 282(6):L1272–8.10.1152/ajplung.00490.2001
    1. Fagan KA, Fouty BW, Tyler RC, Morris KG, Jr, Hepler LK, Sato K, et al. The pulmonary circulation of homozygous or heterozygous eNOS-null mice is hyperresponsive to mild hypoxia. J Clin Invest (1999) 103(2):291–9.10.1172/JCI3862
    1. Balasubramaniam V, Tang JR, Maxey A, Plopper CG, Abman SH. Mild hypoxia impairs alveolarization in the endothelial nitric oxide synthase-deficient mouse. Am J Physiol Lung Cell Mol Physiol (2003) 284(6):L964–71.10.1152/ajplung.00421.2002
    1. Balasubramaniam V, Maxey AM, Morgan DB, Markham NE, Abman SH. Inhaled NO restores lung structure in eNOS-deficient mice recovering from neonatal hypoxia. Am J Physiol Lung Cell Mol Physiol (2006) 291(1):L119–27.10.1152/ajplung.00395.2005
    1. Tang JR, Markham NE, Lin YJ, McMurtry IF, Maxey A, Kinsella JP, et al. Inhaled nitric oxide attenuates pulmonary hypertension and improves lung growth in infant rats after neonatal treatment with a VEGF receptor inhibitor. Am J Physiol Lung Cell Mol Physiol (2004) 287(2):L344–51.10.1152/ajplung.00291.2003
    1. Tourneux P, Markham N, Seedorf G, Balasubramaniam V, Abman SH. Inhaled nitric oxide improves lung structure and pulmonary hypertension in a model of bleomycin-induced bronchopulmonary dysplasia in neonatal rats. Am J Physiol Lung Cell Mol Physiol (2009) 297(6):L1103–11.10.1152/ajplung.00293.2009
    1. Madurga A, Golec A, Pozarska A, Ishii I, Mizikova I, Nardiello C, et al. The H2S-generating enzymes cystathionine beta-synthase and cystathionine gamma-lyase play a role in vascular development during normal lung alveolarization. Am J Physiol Lung Cell Mol Physiol (2015) 309(7):L710–24.10.1152/ajplung.00134.2015
    1. Vadivel A, Alphonse RS, Ionescu L, Machado DS, O’Reilly M, Eaton F, et al. Exogenous hydrogen sulfide (H2S) protects alveolar growth in experimental O2-induced neonatal lung injury. PLoS One (2014) 9(3):e90965.10.1371/journal.pone.0090965
    1. Madurga A, Mizikova I, Ruiz-Camp J, Vadasz I, Herold S, Mayer K, et al. Systemic hydrogen sulfide administration partially restores normal alveolarization in an experimental animal model of bronchopulmonary dysplasia. Am J Physiol Lung Cell Mol Physiol (2014) 306(7):L684–97.10.1152/ajplung.00361.2013
    1. Maden M. Vitamin A and pattern formation in the regenerating limb. Nature (1982) 295(5851):672–5.10.1038/295672a0
    1. Massaro GD, Massaro D. Retinoic acid treatment abrogates elastase-induced pulmonary emphysema in rats. Nat Med (1997) 3(6):675–7.10.1038/nm0697-675
    1. Massaro GD, Massaro D. Retinoic acid treatment partially rescues failed septation in rats and in mice. Am J Physiol Lung Cell Mol Physiol (2000) 278(5):L955–60.
    1. McGowan S, Jackson SK, Jenkins-Moore M, Dai HH, Chambon P, Snyder JM. Mice bearing deletions of retinoic acid receptors demonstrate reduced lung elastin and alveolar numbers. Am J Respir Cell Mol Biol (2000) 23(2):162–7.10.1165/ajrcmb.23.2.3904
    1. Yun EJ, Lorizio W, Seedorf G, Abman SH, Vu TH. VEGF and endothelium-derived retinoic acid regulate lung vascular and alveolar development. Am J Physiol Lung Cell Mol Physiol (2016) 310(4):L287–98.10.1152/ajplung.00229.2015
    1. Choi JW, Herr DR, Noguchi K, Yung YC, Lee CW, Mutoh T, et al. LPA receptors: subtypes and biological actions. Annu Rev Pharmacol Toxicol (2010) 50:157–86.10.1146/annurev.pharmtox.010909.105753
    1. Toews ML, Ediger TL, Romberger DJ, Rennard SI. Lysophosphatidic acid in airway function and disease. Biochim Biophys Acta (2002) 1582(1–3):240–50.10.1016/S1388-1981(02)00177-4
    1. Tager AM, LaCamera P, Shea BS, Campanella GS, Selman M, Zhao Z, et al. The lysophosphatidic acid receptor LPA1 links pulmonary fibrosis to lung injury by mediating fibroblast recruitment and vascular leak. Nat Med (2008) 14(1):45–54.10.1038/nm1685
    1. Zhao J, He D, Su Y, Berdyshev E, Chun J, Natarajan V, et al. Lysophosphatidic acid receptor 1 modulates lipopolysaccharide-induced inflammation in alveolar epithelial cells and murine lungs. Am J Physiol Lung Cell Mol Physiol (2011) 301(4):L547–56.10.1152/ajplung.00058.2011
    1. Chen X, Walther FJ, van Boxtel R, Laghmani EH, Sengers RM, Folkerts G, et al. Deficiency or inhibition of lysophosphatidic acid receptor 1 protects against hyperoxia-induced lung injury in neonatal rats. Acta Physiol (Oxf) (2016) 216(3):358–75.10.1111/apha.12622
    1. Nozik-Grayck E, Suliman HB, Piantadosi CA. Extracellular superoxide dismutase. Int J Biochem Cell Biol (2005) 37(12):2466–71.10.1016/j.biocel.2005.06.012
    1. Delaney C, Wright RH, Tang JR, Woods C, Villegas L, Sherlock L, et al. Lack of EC-SOD worsens alveolar and vascular development in a neonatal mouse model of bleomycin-induced bronchopulmonary dysplasia and pulmonary hypertension. Pediatr Res (2015) 78(6):634–40.10.1038/pr.2015.166
    1. Ahmed MN, Suliman HB, Folz RJ, Nozik-Grayck E, Golson ML, Mason SN, et al. Extracellular superoxide dismutase protects lung development in hyperoxia-exposed newborn mice. Am J Respir Crit Care Med (2003) 167(3):400–5.10.1164/rccm.200202-108OC
    1. Nozik-Grayck E, Suliman HB, Majka S, Albietz J, Van Rheen Z, Roush K, et al. Lung EC-SOD overexpression attenuates hypoxic induction of Egr-1 and chronic hypoxic pulmonary vascular remodeling. Am J Physiol Lung Cell Mol Physiol (2008) 295(3):L422–30.10.1152/ajplung.90293.2008
    1. Collins JJ, Thebaud B. Progenitor cells of the distal lung and their potential role in neonatal lung disease. Birth Defects Res A Clin Mol Teratol (2014) 100(3):217–26.10.1002/bdra.23227
    1. Pierro M, Thebaud B. Mesenchymal stem cells in chronic lung disease: culprit or savior? Am J Physiol Lung Cell Mol Physiol (2010) 298(6):L732–4.10.1152/ajplung.00099.2010
    1. Hogan BL, Barkauskas CE, Chapman HA, Epstein JA, Jain R, Hsia CC, et al. Repair and regeneration of the respiratory system: complexity, plasticity, and mechanisms of lung stem cell function. Cell Stem Cell (2014) 15(2):123–38.10.1016/j.stem.2014.07.012
    1. Balasubramaniam V, Mervis CF, Maxey AM, Markham NE, Abman SH. Hyperoxia reduces bone marrow, circulating, and lung endothelial progenitor cells in the developing lung: implications for the pathogenesis of bronchopulmonary dysplasia. Am J Physiol Lung Cell Mol Physiol (2007) 292(5):L1073–84.10.1152/ajplung.00347.2006
    1. Irwin D, Helm K, Campbell N, Imamura M, Fagan K, Harral J, et al. Neonatal lung side population cells demonstrate endothelial potential and are altered in response to hyperoxia-induced lung simplification. Am J Physiol Lung Cell Mol Physiol (2007) 293(4):L941–51.10.1152/ajplung.00054.2007
    1. Chang YS, Oh W, Choi SJ, Sung DK, Kim SY, Choi EY, et al. Human umbilical cord blood-derived mesenchymal stem cells attenuate hyperoxia-induced lung injury in neonatal rats. Cell Transplant (2009) 18(8):869–86.10.3727/096368909X471189
    1. Aslam M, Baveja R, Liang OD, Fernandez-Gonzalez A, Lee C, Mitsialis SA, et al. Bone marrow stromal cells attenuate lung injury in a murine model of neonatal chronic lung disease. Am J Respir Crit Care Med (2009) 180(11):1122–30.10.1164/rccm.200902-0242OC
    1. van Haaften T, Byrne R, Bonnet S, Rochefort GY, Akabutu J, Bouchentouf M, et al. Airway delivery of mesenchymal stem cells prevents arrested alveolar growth in neonatal lung injury in rats. Am J Respir Crit Care Med (2009) 180(11):1131–42.10.1164/rccm.200902-0179OC
    1. Pierro M, Ionescu L, Montemurro T, Vadivel A, Weissmann G, Oudit G, et al. Short-term, long-term and paracrine effect of human umbilical cord-derived stem cells in lung injury prevention and repair in experimental bronchopulmonary dysplasia. Thorax (2013) 68(5):475–84.10.1136/thoraxjnl-2012-202323
    1. De Paepe ME, Patel C, Tsai A, Gundavarapu S, Mao Q. Endoglin (CD105) up-regulation in pulmonary microvasculature of ventilated preterm infants. Am J Respir Crit Care Med (2008) 178(2):180–7.10.1164/rccm.200608-1240OC
    1. De Paepe ME, Greco D, Mao Q. Angiogenesis-related gene expression profiling in ventilated preterm human lungs. Exp Lung Res (2010) 36(7):399–410.10.3109/01902141003714031
    1. Lassus P, Turanlahti M, Heikkila P, Andersson LC, Nupponen I, Sarnesto A, et al. Pulmonary vascular endothelial growth factor and Flt-1 in fetuses, in acute and chronic lung disease, and in persistent pulmonary hypertension of the newborn. Am J Respir Crit Care Med (2001) 164(10 Pt 1):1981–7.10.1164/ajrccm.164.10.2012036
    1. Ambalavanan N, Novak ZE. Peptide growth factors in tracheal aspirates of mechanically ventilated preterm neonates. Pediatr Res (2003) 53(2):240–4.10.1203/00006450-200302000-00007
    1. Trittmann JK, Peterson E, Rogers LK, Chen B, Backes CH, Klebanoff MA, et al. Plasma asymmetric dimethylarginine levels are increased in neonates with bronchopulmonary dysplasia-associated pulmonary hypertension. J Pediatr (2015) 166(2):230–3.10.1016/j.jpeds.2014.09.004
    1. Mercier JC, Hummler H, Durrmeyer X, Sanchez-Luna M, Carnielli V, Field D, et al. Inhaled nitric oxide for prevention of bronchopulmonary dysplasia in premature babies (EUNO): a randomised controlled trial. Lancet (2010) 376(9738):346–54.10.1016/S0140-6736(10)60664-2
    1. Cole FS, Alleyne C, Barks JD, Boyle RJ, Carroll JL, Dokken D, et al. NIH Consensus Development Conference statement: inhaled nitric-oxide therapy for premature infants. Pediatrics (2011) 127(2):363–9.10.1542/peds.2010-3507
    1. Kinsella JP, Cutter GR, Steinhorn RH, Nelin LD, Walsh WF, Finer NN, et al. Noninvasive inhaled nitric oxide does not prevent bronchopulmonary dysplasia in premature newborns. J Pediatr (2014) 165(6):1104.e–8.e.10.1016/j.jpeds.2014.06.018
    1. Yoder MC, Mead LE, Prater D, Krier TR, Mroueh KN, Li F, et al. Redefining endothelial progenitor cells via clonal analysis and hematopoietic stem/progenitor cell principals. Blood (2007) 109(5):1801–9.10.1182/blood-2006-08-043471
    1. Baker CD, Ryan SL, Ingram DA, Seedorf GJ, Abman SH, Balasubramaniam V. Endothelial colony-forming cells from preterm infants are increased and more susceptible to hyperoxia. Am J Respir Crit Care Med (2009) 180(5):454–61.10.1164/rccm.200901-0115OC
    1. Borghesi A, Massa M, Campanelli R, Bollani L, Tzialla C, Figar TA, et al. Circulating endothelial progenitor cells in preterm infants with bronchopulmonary dysplasia. Am J Respir Crit Care Med (2009) 180(6):540–6.10.1164/rccm.200812-1949OC
    1. Baker CD, Balasubramaniam V, Mourani PM, Sontag MK, Black CP, Ryan SL, et al. Cord blood angiogenic progenitor cells are decreased in bronchopulmonary dysplasia. Eur Respir J (2012) 40(6):1516–22.10.1183/09031936.00017312
    1. Popova AP, Bozyk PD, Bentley JK, Linn MJ, Goldsmith AM, Schumacher RE, et al. Isolation of tracheal aspirate mesenchymal stromal cells predicts bronchopulmonary dysplasia. Pediatrics (2010) 126(5):e1127–33.10.1542/peds.2009-3445
    1. Chang YS, Ahn SY, Yoo HS, Sung SI, Choi SJ, Oh WI, et al. Mesenchymal stem cells for bronchopulmonary dysplasia: phase 1 dose-escalation clinical trial. J Pediatr (2014) 164(5):966.e–72.e.10.1016/j.jpeds.2013.12.011
    1. Hilgendorff A, Reiss I, Ehrhardt H, Eickelberg O, Alvira CM. Chronic lung disease in the preterm infant. Lessons learned from animal models. Am J Respir Cell Mol Biol (2014) 50(2):233–45.10.1165/rcmb.2013-0014TR

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