Biomedical subjects

James M Greenberg

Publications and source records attributed to James M Greenberg.

6 recordsLinked to original sources

PubMed2006

Lymphangiogenesis in the developing lung promoted by VEGF-A.

Understanding the basic processes of late-stage pulmonary vascular development is essential as this period corresponds to the stage when preterm infants have increased chance of survival. During this period, refinement of the gas exchange unit leads to close apposition of the capillary vasculature and airway epithelium through thinning of the mesenchyme, formation of alveolar septae and functional adaptation of endothelial cells into vessels including pulmonary lymphatics. The pulmonary lymphatic network promotes efficient gas exchange through maintaining interstitial fluid balance. Through conditional transgene regulation, we found that a modest, pathologically relevant increase in vascular endothelial growth factor A (VEGF-A) in distal lung during only the perinatal period adversely affected final refinement of the gas exchange unit. VEGF-A induction disrupted the established vascular network, increased endothelial cell number, altered endothelial ultrastructure and reduced mesenchymal thinning. In addition, VEGF-A induction caused a 3-fold increase in small vessels identified as lymphatics in distal lung. mRNA levels of lymphangiogenic factors VEGF-D/-C were unchanged, while levels of the cognate receptor VEGFR-3 increased. The responses to VEGF-A induction in the perinatal period differ from those during early lung development when endothelial migration, but not proliferation altered initial vascular patterning (Akeson, A.L., Greenberg, J.M., Cameron, J.E., Thompson, F.Y., Brooks, S.K., Wiginton, D., Whitsett, J.A., 2003. Temporal and spatial regulation of VEGF-A controls vascular patterning in the embryonic lung. Dev. Biol. 264, 443-455). The late-stage response resembles that of adult lung to VEGF-inducing stimuli including injury and disease. These data suggest that VEGF-A influences the balance between development of blood and lymphatic vasculature during lung organogenesis.

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PubMed2004

Vascular endothelial growth factor-A induces prenatal neovascularization and alters bronchial development in mice.

Pulmonary vascular development requires precise temporal and spatial expression of vascular endothelial growth factor-A (VEGF-A). Diminished expression of VEGF-A in preterm infants may contribute to the pathophysiology of respiratory distress syndrome. Because exogenous replacement of VEGF-A has been proposed as a therapeutic for respiratory distress syndrome, we used conditional activation of VEGF-A in bronchial epithelial cells to assess the effects of increase of VEGF-A on lung morphogenesis and survival in the developing mouse. Increased expression of VEGF-A in late stages of gestation was lethal at birth. Although born alive, the pups remained cyanotic and failed to establish respiration. Vascular and epithelial morphology of the main bronchus and primary and secondary bronchi were altered with neovascularization of the mucosal folds and partial obstruction of the conducting airways. Erythrocytes were observed in the pulmonary interstitium and in intra-alveolar spaces, indicating vascular leak. Increased diameter of pulmonary arteries and angioectatic structures were observed in VEGF-expressing mice. Bronchial expression of VEGF-A alters late-stage morphogenesis of conducting airways and primary bronchial arteries and causes respiratory failure at birth.

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PubMed2004

Slit and robo expression in the developing mouse lung.

Mammalian lung development is mediated through complex interactions between foregut endoderm and surrounding mesenchyme. As airway branching progresses, the mesenchyme undergoes dramatic remodeling and differentiation. Little is understood about the mechanisms that direct mesenchymal organization during lung development. A screen for candidate genes mediating this process identified Slit, a ligand for the Roundabout (Robo) receptor previously associated with guidance of axonal projections during central nervous system development. Here, we demonstrate by in situ hybridization that two Slit genes (Slit-2 and Slit-3) and two Robo genes (Robo-1 and Robo-2) are expressed in fetal lung mesenchyme. Slit-2 and Robo-1 expression is present throughout mesenchyme at midgestation and is not detectable by newborn day 1. Slit-3 and Robo-2 expression is restricted to specific, complementary subsets of mesenchyme. Robo-2 is expressed in mesenchymal cells immediately adjacent to large airways, whereas Slit-3 expression predominates in mesenchyme remote from airway epithelium. The temporal and spatial distribution of Slit and Robo mRNAs indicate that these genes may direct the functional organization and differentiation of fetal lung mesenchyme.

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PubMed2004

Intrapartum management of severe fetal airway obstruction.

OBJECTIVE: To review our experience with the planned intrapartum management of fetuses with suspected severe airway obstruction. METHODS: Retrospective review of prenatal presentations, intrapartum airway procurement methods, outcomes, and complications. RESULTS: All cases (N = 11) at our tertiary airway referral institution between 1995 and 2002 were reviewed. Obstruction was secondary to giant cervicofacial lymphangiomas (5), teratomas (2), epignathis (1), epulis (1), conjoined fetus (1), and tracheal foreign body (1). Elective cesarean delivery of the entire fetus was performed while maintaining fetal-placental circulation as long as possible. We found it necessary to deliver the entire fetus to improve airway exposure and decrease maternal hemorrhage. The airway was secured effectively in all cases. CONCLUSIONS: Although full cesarean delivery of the fetus significantly reduces fetal-placental circulation times, in comparison with the formal ex utero intrapartum treatment (EXIT) procedure, airway access is improved, maternal complications may be decreased, and high airway procurement success is still safely achieved.

Airway Obstruction↗

PubMed2003

Temporal and spatial regulation of VEGF-A controls vascular patterning in the embryonic lung.

Vascular endothelial growth factor-A (VEGF-A) is required for vascular development throughout the embryo and has been proposed to play an important role in pulmonary vascular patterning. Expressed by the embryonic respiratory epithelium, VEGF-A signals endothelial cells within the splanchnic mesenchyme. To refine understanding of the spatial and temporal role of VEGF-A in lung morphogenesis, isoform VEGF164 was expressed under conditional control in distal and proximal airway epithelial cells. Unexpectedly, increased expression of VEGF164 in distal lung disrupted peripheral vascular net assembly and arrested branching of airways tubules without altering endothelial cell proliferation or apoptosis. Peripheral airway branching and vascular smooth muscle patterning were also altered. In contrast, expression of VEGF164 by epithelial cells of the conducting airways caused atypical evaginations of small capillary-like vessels into large airways but did not alter peripheral vascular net assembly or branching morphogenesis. These data demonstrate that the differential response of endothelial cells in distal vascular beds and large central blood vessels is established early in lung development. Precise temporal and spatial expression of VEGF-A is required for vascular patterning during lung morphogenesis. Disruption of pulmonary vascular assembly perturbs reciprocal interactions with epithelium leading to altered airway branching morphogenesis.

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PubMed2002

Mesenchymal expression of vascular endothelial growth factors D and A defines vascular patterning in developing lung.

The lung has specific vascular patterning requirements for effective gas exchange at birth, including alignment of airways and blood vessels and lymphatic vessels. Vascular endothelial growth factors (VEGF) are potent effectors of vascular development. We examined the temporal and spatial expression of VEGF-D and specific VEGF-A isoforms at each stage of lung development. VEGF-D, expressed only by cadherin-11-positive cells of the mesenchyme, is first detected at embryonic day (E) 13.5, a period of active vasculogenesis. VEGFR-3, its cognate receptor, is detected earlier on days E11.5 to E14.5, in both blood vessels and lymphatic vessels and later, on day E17.5, in only lymphatic vessels. VEGF-A is expressed in the mesenchyme throughout lung development and also by the epithelium midway through organogenesis. Before E14, the predominant forms of VEGF-A are the soluble isoforms, VEGF-A120 and 164. Not until E14.5 do epithelial cells at the tips of expanding airways express VEGF-A, including VEGF-A188, an isoform with high affinity for extracellular matrix. Our results demonstrate unique temporal and spatial expression of VEGF-D and specific VEGF-A isoforms during lung development and suggest these related factors have distinct functions in vascular and lymphatic patterning of the lung.

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