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Burridge K and Wennerberg K (2004) Rho and rac take center stage. Cell 116: 167179. Cai H, Griendling KK, and Harrison DG (2003) The vascular NAD(P)H oxidases as therapeutic targets in cardiovascular diseases. Trends in Pharmacological Sciences 24: 471478. Cross AR and Segal AW (2004) The nadph oxidase of professional phagocytes prototype of the nox electron transport chain systems. Biochimica et Biophysica Acta 1657: 122. Fisher AB, Chien S, Barakat AI, and Nerem RM (2001) Endothelial cellular response to altered shear stress. American Journal of Physiology. Lung Cellular and Molecular Physiology 281: L529L533. Forman HJ and Torres M (2002) Reactive oxygen species and cell signaling: respiratory burst in macrophage signaling. American Journal of Respiratory and Critical Care Medicine 166: S4S8. Griendling KK, Sorescu D, and Ushio-Fukai M (2000) NAD(P)H oxidase: role in cardiovascular biology and disease. Circulation Research 86: 494501. Groemping Y, Lapouge K, Smerdon SJ, and Rittinger K (2003) Molecular basis of phosphorylation-induced activation of the NADPH oxidase. Cell 113: 343355. Hoidal JR, Brar SS, Sturrock AB, et al. (2003) The role of endogenous NADPH oxidases in airway and pulmonary vascular smooth muscle function. Antioxidants and Redox Signaling 5: 751758. Jones RD, Hancock JT, and Morice AH (2000) NADPH oxidase: a universal oxygen sensor? Free Radical Biology and Medicine 29: 416424. Lambeth JD (2004) Nox enzymes and the biology of reactive oxygen. Nature Reviews: Immunology 4: 181189. Patil S, Bunderson M, Wilham J, and Black SM (2004) Important role for Rac1 in regulating reactive oxygen species generation and pulmonary arterial smooth muscle cell growth. American Journal of Physiology: Lung Cellular and Molecular Physiology 287: L1314L1322. Quinn MT and Gauss KA (2004) Structure and regulation of the neutrophil respiratory burst oxidase: comparison with nonphagocyte oxidases. Journal of Leukocyte Biology 76: 760781. Takeya R and Sumimoto H (2003) Molecular mechanism for activation of superoxide-producing NADPH oxidases. Molecules and Cells 16: 271277. Vignais PV (2002) The superoxide-generating nadph oxidase: structural aspects and activation mechanism. Cellular and Molecular Life Sciences 59: 14281459.

Acute Lung Injury

Acute lung injury (ALI) is a syndrome characterized by widespread impairment of the small blood vessels in the lung resulting in noncardiogenic pulmonary edema and alterations in pulmonary gas exchange. Severe manifestations are termed the acute respiratory distress syndrome (ARDS). Etiology of the syndrome can be classied as either direct injury to the lungs such as due to acid aspiration or an indirect injury such as ALI associated with systemic infection. A consistent nding is the presence of large numbers of inammatory cells in the lung. It has been suggested that increased ROS generation by activated PMNs possibly combined with decreased antioxidant capacity plays a central role in pathogenesis of ARDS. By this theory, the NADPH oxidase and its activation generate extracellular ROS, which damage normal cellular constituents. ROS generation by endothelium or other lung cells may contribute to the oxidant load. Although this hypothesis has some experimental support, suppression of PMNs has given equivocal results for severity of injury, and antioxidant therapy has not yet proven useful in amelioration of the disease.
See also: Acute Respiratory Distress Syndrome. Apoptosis. Leukocytes: Neutrophils. Transcription Factors: NF-kB and Ikb.

Further Reading
Babior BM, Lambeth JD, and Nauseef W (2002) The neutrophil nadph oxidase. Archives in Biochemistry and Biophysics 397: 342344. Bengtsson SH, Gulluyan LM, Dusting GJ, and Drummond GR (2003) Novel isoforms of NADPH oxidase in vascular physiology and pathophysiology. Clinical and Experimental Pharmacology and Physiology 30: 849854. Bokoch GM and Knaus UG (2003) NADPH oxidases: not just for leukocytes anymore!. Trends in Biochemical Sciences 28: 502508.

NEONATAL CIRCULATION
J A Adams, Mount Sinai Medical Center, Miami Beach, FL, USA
& 2006 Elsevier Ltd. All rights reserved. highlighting the important mediators responsible for maintenance of the vascular resistance in utero. Transition to the extrauterine environment will be reviewed with emphasis on the balance between vasoconstrictor and vasodilators and the effects of various stressors on this transition. To simplify the understanding of how pathological processes affect the pulmonary vascular system, these pathological processes will be grouped and examples provided based on their type and time of occurrence: (1) induced intrauterine vascular abnormalities, (2) anatomical anomalies, (3) abnormal transition to extrauterine life, and (4) abnormal development of the postnatal circulation. An understanding of the importance of how various diseases affect vascular development depending upon the timing within lung

Abstract
This article summarizes the development of the neonatal pulmonary circulation. The complexity of such circulation during development and the factors responsible for structural and biochemical growth will be discussed. The fetal circulation will be reviewed from an anatomical and biochemical perspective

NEONATAL CIRCULATION 85
development and the biology of the pulmonary vascular endothelium will likely lead to important therapeutic interventions in the near future that will include molecular biology and endothelial conditioning strategies.

walls of the pulmonary artery, veins (vasa vasorum), and nerves.

Vasculogenesis and Angiogenesis

Development of the Circulatory System

Adaptation to the extrauterine environment requires morphologically appropriate pulmonary vascular development, both arterial and venous, and adequate biochemical and biophysical response of this vasculature. The pulmonary vascular growth closely follows the stages of pulmonary parenchymal growth and development (Figure 1). At 4 weeks of human development, an endodermal lung bud arises from the primitive gut, which is surrounded by mesenchymal vascular network. As gestation progresses, the vessels accompany the developing airways branch synchronously with airways branching. The pulmonary veins arise from the mesenchyme of the lung septa and ultimately join the left atrium. Bronchial arteries arise from the descending aorta, intercostals, subclavian, or internal mammary arteries. There are two classes of bronchial arteries: (1) extrapulmonary, which give off small branches to the esophagus, mediastinal tissue, hiliar lymph nodes, and lobar bronchi and (2) intrapulmonary, which distribute blood to the supporting tissue and structures of the intralobal bronchi (mucous membranes, muscle, perichondrium, secretory glands), pulmonary pleura,

Two important processes that contribute to the development of the pulmonary vasculature are vasculogenesis (differentiation and segregation of angioblasts from the mesoderm) and angiogenesis (the sprouting of new vessels from pre-existing vessels or vascular channels). In addition to vasculogenesis and angiogenesis a third process, fusion, is ultimately necessary to connect the angiogenic and vasculogenic vessels and expand the vascular network. Induction of local growth factors such as basic broblast growth factor (FGF), transforming growth factor beta (TGF-b), and platelet-derived growth factor (PDGF) are all important for angiogenesis, endothelial proliferation, collagen production, and smooth muscle and cell differentiation. Normal vascular development may also require the expression of angiostatic molecules such as endothelial monocyte activating peptide-2 (EMAP-2), which induces endothelial apoptosis. In addition, other stimuli contribute to both alveolar and vascular growth and development and in part involve cross-talk of paracrine signals between the epithelium and mesenchyme. An example of one such signal is vascular endothelial growth factor (VEGF). The exact stimuli for production of these local

Fetal stage

Airway trachea

Arterial development

Embryonic 07 weeks

Extrapulmonary artery 34 days Lobar arteries 44 days Bronchi Preacinar arteries 1123 generations conventional plus supernumeraries Bronchioli 517 weeks Intra-acinar arteries 35 generations 1825 weeks Alveolar duct arteries 23 generations 25 weeks18 months Alveolar capillaries 30 weeks18 yrs Acinus

Pseudoglandular 717 weeks

Canalicular 1727 weeks

Respiratory bronchioli Alveolar ducts

Saccular/Alveolar 28 weeks term Alveoli pleura

Figure 1 Stages of lung airway and vascular development. Adapted from Hislop A (2005) Developmental biology of the pulmonary circulation. Paediatric Respiratory Reviews 6: 36, with permission from Elsevier.

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factors remain to be elucidated, but they are clearly important in vascular development. Initially the endothelial cells form channels but as development progresses these channels acquire a smooth muscle layer, with the ability to regulate ow and vascular tone. The smooth muscle cells are derived from the adjacent bronchial smooth muscle, and later from the mesenchyme. The smooth muscle cells of the airways, arteries, and veins show progressive and gradual maturation of their cytoskeletal structure. The arterial smooth muscle cells change structurally during development and continue postnatally (Figure 2). Normal postnatal pulmonary arterial development can be divided into three structural stages: Stage I: adaptation to extrauterine life from birth to approximately 4 days. Stage II: structural stabilization that lasts until 34 weeks of age. Stage III: growth that continues to adulthood. During stage I, endothelial cells become thinner and show less overlap, vessel wall becomes thinner, and lumen diameter increases. This stage is characterized by dilatation and recruitment which occurs in the rst 24 h of life in the nonmuscular and partially muscular precapillary bed. There is an increase in cell length, the cells spread out within the vessel wall to increase lumen diameter and lower vascular resistance. Structural changes during stage II

include the deposit of connective tissue around the cells in order to x themselves to the new wall structure. During stage III, the intrapulmonary arteries increase in size and their wall thickness increases. Cross-sectional area of the precapillary bed is increased to accommodate a larger cardiac output, while maintaining a low vascular resistance. In addition, connective tissue increases and the proportion of the different types of interstitial connective tissue also changes with age. This affects the mechanical properties of the vessel wall, with greater structural stiffness. Additionally, regulation of lung vascular morphogenesis appears to be inuenced by oxygen tension. Hypoxia is an important regulator of both vasculogenesis and angiogenesis. In vitro experiments and fetal lung explant studies suggest that exposure to normoxic environments of fetal mammalian cells can be detrimental to embryonic development.

The Fetal Circulation

During fetal life, pulmonary vascular resistance (PVR) is greater than systemic vascular resistance. Less than 10% of the combined right and left cardiac output is directed to the pulmonary circulation. The factors responsible for the increase in PVR during fetal life include decreased intrauterine oxygen tension, decrease in vascular cross-sectional area, accumulation of the metabolic products of the

Adult

Child

Fetus

19 yrs 11 yrs 10 yrs 5 yrs 4 yrs 3 yrs 18 mths 10 mths 4 mths 3 days 40 wks 38 wks 36 wks 28 wks Alveolar ducts

Terminal bronchiolus

Respiratory bronchioli

Alveoli

Figure 2 Appearance and extension of the muscle in the wall of intra-acinar arteries as a function of age. Adapted from Haworth SG (1992) Development of the Pulmonary Circulation. In: Polin and Fox Fetal and Neonatal Physiology, vol. 1, p. 672. Philadelphia: Saunders, with permission from Elsevier.

NEONATAL CIRCULATION 87

arachidonic acid pathway, and endothelin. Thus, the fetal pulmonary circulation is a high-resistance, lowow circuit. The ow of blood during fetal life can be categorized as two parallel circuits. Since fetal pulmonary vascular resistance is high, most of the venous return from the inferior and superior vena cava is shunted via the foramen ovale and the ductus arteriosus to the systemic circulation. Once in the descending

aorta, blood ows via the umbilical arteries to the placenta where oxygenation and removal of CO2 takes place to return via the inferior vena cava through the umbilical vein. The low systemic vascular resistance in the fetus is due to the very low vascular resistance of the placenta. An additional shunt in the liver (ductus venosus) combines umbilical venous blood with systemic venous blood, with return to the right heart (Figures 35).
Ductus arteriosus

SVC PA

Foramen ovale RA

LA RV

Ductus venosus

Aorta

Umbilical vein

Umbilical arteries

Figure 3 Fetal circulation. Umbilical veins carry oxygenated blood from the placenta, while the two umbilical arteries carry systemic blood to the placenta for oxygenation. LA, left atrium; PA, pulmonary artery; RA, right atrium; RV, right ventricle; SVC, superior vena cava. Adapted from Bloom RS (2002) Delivery room resuscitation of the newborn. In: Fanaroff A and Martin RJ (eds.) Neonatal Perinatal Medicine, 7th edn., vol. 1, p. 417. St Louis: Mosby, with permission from Elsevier.

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Ductus arteriosus

Right heart

Left heart

Body

Foramen ovale

Figure 4 Diagram of the fetal parallel circulation. Note that the majority of the right ventricular output goes via the ductus arteriosus to supply the brain and the rest of the body. The placenta performs the functions of oxygenation and carbon dioxide removal.

Transition to the Extrauterine Environments and Postnatal Blood Flow

At birth, several events and local and systemic factors intervene to change the pulmonary circulation from a high-resistance low-ow circuit to a low-resistance higher-ow one. Further, the systemic circulation changes from a low-resistance to a higher-resistance circuit. Upon clamping the umbilical vessels, the placental circulation is no longer operative, and thus systemic vascular resistance increases (Figure 6). The mechanisms responsible for the postnatal fall in PVR are uncertain but the initial rapid dilatation of the pulmonary vasculature is stimulated by rhythmic ventilation, increase in oxygen tension, and increase in vascular shear stress. The sudden increase in ow and shear stress lead to production of potent vasodilators such as endothelial derived nitric oxide (eNO), prostacyclin (PGI2), and bradykinin. Subsequently, maintenance of low-pressure system in the pulmonary vasculature becomes a balance between vasodilators (eNO) and vasoconstritors (endothelin-I) (Table 1). Functional closure of the ductus arteriosus also occurs over the initial 2472 h after birth. Factors that are responsible for this initial functional closure

include increased arterial O2 tension, plasma catecholamine levels, suppression of PGI2, and switching off of prostaglandin E receptors. Complete anatomical closure of the ductus can take 23 weeks. The transition from fetal to neonatal circulation involves several mechanisms involving mechanical and humoral factors, which act together to promote transition from a parallel circulation to a series one.

Pathophysiology
To simplify the understanding of how pathological processes affect the pulmonary vascular system, these pathological processes can be based upon their type and time of occurrence: (1) induced intrauterine vascular abnormalities, (2) anatomical anomalies, (3) abnormal transition to extrauterine life, and (4) abnormal development of the postnatal circulation.
Induced Intrauterine Vascular Anomalies

Induced vascular abnormalities have been documented after intrauterine exposure to a host of medications. Prostaglandin inhibition, such as occurs with prenatal administration of nonsteroidal

NEONATAL CIRCULATION 89

Right heart

Left heart

Body

Figure 5 Diagram of the postnatal circulation in series. The ductus arteriosus and foramen ovale are no longer functional, and thus the entire output from the right ventricle goes to the lungs. The left ventricular output supplies the brain and the rest of the body. Oxygenation and carbon dioxide removal is solely achieved in the lungs.

Pulmonary 550 500 400 350 300 250 200 150 100 Birth 26 612 Age Right 450 Left Ductal shunt

Systemic 250 200 150 100 50 0 1225 2554 (hrs)

Figure 6 Changes in vascular resistance and ventricular output as a function of age in hours. Note the very high pulmonary vascular resistance and low systemic vascular resistance at birth. The decrease in pulmonary vascular resistance occurs abruptly after birth, and achieves its adult levels early. The increase in systemic vascular resistance also occurs abruptly and decreases over time. Yellow line depicts the right ventricular output and the black line the left ventricular output, changes over age in hours. The difference in ventricular outputs is accounted by the presence of a ductal shunt in the rst 24 h of age. Adapted from Nelson N (1999) The onset of respiration. In: Avery G, Fletcher MA, and MacDonald MG (eds.) Neonatology: Pathophysiology and Management of the Newborn, 5th edn., p. 264. Baltimore: Lippincott Williams & Wilkins, with permission.

Ventricular output (ml/kg/min)

Resistance (mmHg/l/kg/min)

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Table 1 Mediators of pulmonary vascular tone in fetal and transitional circulation Vasoconstrictors: maintain high fetal PVR Norepinephrine a-Adrenergic stimulation Hypoxia Endothelin Thromboxane Leukotrienes PAF PDF2a Vasodilators: decrease PVR during transition PGI2, PGD2, PGE2 Nitric oxide CGMP Oxygen Adenosine ATP Bradykinin

syndrome), thoracic dystrophy, and idiopathic pulmonary hypoplasia have a similar reduction in their pulmonary vascular bed. The above pathologies share the commonality of abnormal lung growth.
Abnormal Transition to Extrauterine Life

ATP, adenosine triphosphate; cGMP, cyclic guanosine monophosphate; PAF, platelet-activating factor; PDF, platelet-derived factor; PG, prostaglandin; PVR, pulmonary vascular resistance. Adapted from Dukarm RC, Steinhorn RH, and Morin FC (1996) The normal pulmonary vascular transition at birth. Clinics in Perinatology 23(4): 714, with permission from Elsevier.

anti-inammatory agents, can produce pulmonary vascular hypoplasia. Thalidomide, now banned for use in pregnancy, is a well-known antiangiogenic agent; exposure of human and animals prenatally leads to pulmonary vascular dysregulation with vascular hypoplasia. Antenatal administration of corticosteroids accelerates lung maturation of type II pneumocytes, thinning of the double capillary loops during sacular and alveolar stages, and partial suppression of the formation of secondary septa. Moreover, corticosteroids may also decrease somatic and lung growth. However, antenatal treatment with corticosteroids in humans does not appear to affect lung function as measured at 7 years of age. Angiotensin converting enzyme inhibitor (ACE-I) drugs during gestation have been associated with high risk of fetal morbidity, intrauterine growth retardation, oligohydramnios, and renal failure. Pulmonary hypoplasia has also been reported and the use of these drugs should be avoided during pregnancy. In general, the above-mentioned drugs administered during pregnancy produce pulmonary vascular dysregulation and dysmorphogenesis.
Anatomical Anomalies

Because of the temporal and physical proximity and interaction of lung development on airway and vascular growth, it is not surprising that lung developmental pathologies also affect the pulmonary vasculature. In congenital diaphragmatic hernia (CDH), there is an equal reduction of arteries and airway numbers. These newborns also have pulmonary hypertension with an increase in arterial wall thickness. Newborns with renal agenesis (Potter

The hallmark of an abnormal transition to extrauterine life is persistent pulmonary hypertension of the newborn (PPHN). This is dened as a failure of the normal pulmonary vascular relaxation at or shortly after birth which results in increased impedance to pulmonary blood ow such that pulmonary vascular pressure exceeds systemic vascular resistance. The end result is that deoxygenated blood is shunted via the foramen ovale and ductus arterious to the systemic circulation. Perinatal stressors that can produce PPHN include hypoxia, hypoglycemia, cold stress, sepsis, and direct lung injury. In the initial course of PPHN the pulmonary vasospasm is dynamic, with labile ow via the pulmonary circuit and right-to-left shunting. However, in time this dynamic vasospasm is ultrastructurally transduced to thickened vascular media with hyperplasia and hypertrophy of the smooth muscle layer and increased extracellular matrix deposition, thereby producing a xed vascular resistance. While the latter biphasic response is a well-known response, the timeframe of disease progression varies between different pathophysiologies. Hypoxia produces endothelial dysfunction, with dysfunction in the regulation of the endothelin-1/eNO balance in favor of the vasoconstrictor effect of endothelin-1. Chronic hypoxia has been shown to inhibit the postnatal maturation of the pulmonary artery relaxation by both endothelium-dependent and -independent means and impairment in eNO release and expression. Chronic hypoxia also impairs the normal course of cardiovascular transition since the rapid change in smooth muscle cytoskeletal architecture in the vascular media from densely shaped to elongated shape fails to occur. In addition to the hypoxic pulmonary vasoconstriction produced by direct lung injury such as occurs in meconium aspiration or pneumonia, these conditions may alter the cyclooxygenase pathway. This causes increased thromboxane/prostacyclin ratio, upregulation of cyclooxygenase-2, and activation of inducible nitric oxide synthase leading to prolonged production of large amounts of nitric oxide. Inammatory mediators such as cytokines that are produced during direct lung injury further amplify the pulmonary hypertension by causing vascular smooth muscle contraction and arterial brosis. The end result of this complicated cascade is further endothelial

NEONATAL CIRCULATION 91

dysfunction and ultimately vascular remodeling and xed vascular resistance. Early stages of dynamic pulmonary vasospasm appear to respond to the therapeutic use of inhaled nitric oxide; however, as xed vascular resistance occurs, inhaled nitric oxide and other therapies are less likely to be successful. It is beyond the scope of this article to discuss therapeutic modulation of the pulmonary vasculature.
Abnormal Development of the Postnatal Circulation

(TGF-b) Family of Molecules. Vascular Endothelial Growth Factor.

Further Reading
Bloom RS (2002) Delivery room resuscitation of the newborn. In: Fanaroff A and Martin RJ (eds.) NeonatalPerinatal Medicine, 7th edn., vol. 1, p. 417. St Louis: Mosby. Boels PJ, Deutsch J, Gao B, and Haworth SG (2001) Perinatal development inuences mechanisms of bradykinin-induced relaxations in pulmonary resistance and conduit arteries differently. Cardiovascular Research 51: 140150. Bourbon J, Boucherat O, Chailley-Heu B, and Delacourt C (2005) Control mechanism of the lung alveolar development and their disorders in bronchopulmonary dysplasia. Pediatric Research 57: 38R46R. Dakshinamurti S (2005) Pathophysiologic mechanism of persistent pulmonary hypertension of the newborn. Pediatric Pulmonology 39: 492503. Dukarm RC, Steinhorn RH, and Morin FC III (1996) The normal pulmonary vascular transition at birth. Clinics in Perinatology 23: 711726. Fanaroff AA and Martin RJ (2002) NeonatalPerinatal Medicine: Diseases of the Fetus and Infant. St Louis: Mosby. Ghanayem NS and Gordon JB (2001) Modulation of pulmonary vasomotor tone in the fetus and neonate. Respiratory Research 2: 139144. Hall SM, Hislop A, and Haworth SG (2002) Origin, differentiation, and maturation of human pulmonary veins. American Journal of Respiratory Cell and Molecular Biology 26: 333340. Haworth SG (1992) Development of the Pulmonary Circulation. In: Polin and Fox Fetal and Neonatal Physiology, vol. 1, p. 672. Philadelphia: Saunders. Hislop A (2005) Developmental biology of the pulmonary circulation. Paediatric Respiratory Reviews 6: 3543. Kotecha S (2000) Lung growth: implications for the newborn infant. Archives of Disease in Childhood Fetal and Neonatal Edition 82: F69F74. Lakshminrusimha S and Steinhorn RH (1999) Pulmonary vascular biology during neonatal transition. Clinics in Perinatology 26: 601619. Nelson N (1999) The onset of respiration. In: Avery G, Fletcher MA, and MacDonald MG (eds.) Neonatology: Pathophysiology and Management of the Newborn, 5th edn., p. 264. Baltimore: Lippincott Williams & Wilkins. Parker T and Abman SH (2003) The pulmonary circulation in bronchopulmonary dysplasia. Seminars in Neonatology 8: 5162. Perreault T and Coceani F (2003) Endothelin in the perinatal circulation. Canadian Journal of Physiology and Pharmacology 81: 644653. Polin RA and Fox WW (1992) Fetal and Neonatal Physiology. Philadelphia: Saunders. Stenmark KR and Abman SH (2005) Lung vascular development: implications for the pathogenesis of bronchopulmonary dysplasia. Annual Review of Physiology 67: 623661. Xue C, Reynolds PR, and Johns RA (1996) Developmental expression of NOS isoforms in fetal rat lung: implications for transitional circulation and pulmonary angiogenesis. American Journal of Physiology: Lung Cellular and Molecular Physiology 270: L88L100. Ziegler JW, Ivy D, Kinsella JP, and Abman SH (1995) The role of nitric oxide endothelin and prostaglandins in the transition of the pulmonary circulation. Clinics in Perinatology 22: 387403.

The pathologies that comprise abnormal development of the postnatal circulation have a commonality of potentially irreversible vascular remodeling. The substrate is most often an immature lung which has undergone mechanical ventilatory support, exposure to high concentrations of alveolar oxygen, inammation, volutrauma, and barotrauma. This leads to underdevelopment or maldevelopment of both lung parenchyma and vasculature. An important example of this process is chronic lung disease (CLD) in premature infants or bronchopulmonary dysplasia (BPD). The risk of CLD increases with decreasing birthweight and gestation, with an incidence of greater than 85% in newborns born with 500 700 g. The developmental timing of the lung injury is a critical factor. In addition to altered pulmonary structure of increased smooth cell proliferation, altered vasoreactivity, and impaired metabolic endothelial function, there is decreased aleveolarization and angiogenesis. It is therefore not surprising that pulmonary hypertension is a common nding in CLD.

Conclusions
It is apparent that normal transition to the extrauterine environment requires normal development of the vascular system, adequate biochemical and biophysical response of this vasculature, and the absence of either intrauterine or postnatal insults. Control and modulation of the PVR during deranged conditions remains a formidable research problem. Understanding the complexity of endothelial function and dysfunction and the interdependence of each factor on pulmonary vascular growth (both arterial and venous) will undoubtedly lead to new therapies and interventions.
See also: Bronchopulmonary Dysplasia. Fibroblast Growth Factors. Lung Development: Overview. Platelet-Derived Growth Factor. Pulmonary Vascular Remodeling. Transforming Growth Factor Beta