Akeson Lab
 |
| Transgenic mice expressing the reporter gene β-galactosidase were used to assess the effect of VEGF on embryonic mouse lung vascular development. Whole-mount analysis of E12.5 lungs demonstrates a vascular network of endothelial cells (in blue) throughout the lung (A-C). When VEGF was overexpressed by distal airway epithelial cells (epi)(D-F), endothelial cells were absent from the mesenchyme surrounding the airway tubules. Large vessels running parallel to the main stem bronchus were unaltered (arrows). From Akeson et al Developmental Biology 264:443-455, 2003. (Click image to enlarge.) |
Ann L. Akeson, PhD
Division of Pulmonary Biology
The research in my laboratory focuses on the identification and analysis of cellular and molecular determinants of pulmonary vascular and lymphatic pattern formation and alveolar-capillary interactions. In the lung precise alignment of airway epithelium and capillaries is required for gas exchange. Small deviations of the alignment of airway and vascular network can result in catastrophic developmental and functional problems for newborn children, including alveolar capillary dysplasia. In addition, neonatal chronic lung disease associated with premature birth evolves from disrupted development of pulmonary vascular-epithelial interactions. To achieve appropriate alignment, during lung formation there is a dynamic relationship between the branching airways and the developing vascular network, involving essential cellular and molecular factors. Of particular interest to us in analysis of lung development are two members of the vascular endothelial growth factor family, VEGF-A and VEGF-D.
Using mouse transgenic systems with lung specific induction and inhibition of VEGF, we have shown that VEGF expressed by the airway epithelium, generates a morphogenic gradient, attracting endothelial cells of the expanding capillary network. We are testing the hypothesis that VEGF-D may play a similar role in lymphatic specification and patterning. Cell-based and in vivo model systems are used to assess signaling pathways and transcriptional regulation involved in VEGF-induced endothelial cell specification and patterning.
We have used microarray analysis to identify additional candidates required for vascular specification. These include Slit (secreted leucine-rich repeat-containing protein) and its receptor Robo (roundabout). These proteins regulate axonal guidance but are also expressed in developing lung. We are testing the hypothesis that Slit/Robo interactions "guide" patterning of the developing pulmonary vascular network. In addition we are exploring the role of the transcription factors Nfat and Prox in the determination of lymphatic endothelial cell lineage.
Recent and Current Graduate Students
Lynette Mendoza, MS Molecular and Developmental Biology, June 2003
Thesis The effects of VEGF-A on sFLT-1 Expression in the Developing Lung
Bradford Mallory, PhD Cell and Molecular Biology, 2005
Dissertation VEGF-A/VEGF-D Regulation of Pulmonary Lymphatic Specification and Function
Rishikesh Kulkarni, PhD student in Cell, Cancer and Molecular Biology
Dissertation Transcriptional regulation of lymphatic endothelial cell specification.
Recent Publications
Akeson AL, Wetzel B, Thompson FY, Brooks SK, Paradis H, Gendron RL, Greenberg JM. Embryonic vasculogenesis by endothelial precursor cells derived from lung mesenchyme. Dev Dynamics 217:11-23, 2000.
Akeson AL, Brooks SK, Thompson FY and Greenberg JM. In vitro model for developmental progression from vasculogenesis to angiogenesis with a murine endothelial precursor cell line, MFLM-4. Microvascular Research 61:75-86, 2001.
Greenberg JM, Thompson FY, Brooks SK, Shannon JM, McCormick-Shannon K, Cameron JE, Mallory BP, Akeson AL. Mesenchymal expression of vascular endothelial growth factors D and A defines vascular patterning I developing lung. Dev Dynamics 224:144-153, 2002.
Akeson AL, Greenberg JM, Cameron JE, Thompson FY, Brooks SK, Wiginton D, Whitsett JA. Temporal and spatial regulation of VEGF-A controls vascular patterning in the embryonic lung. Developmental Biology 264:443-455, 2003.
Le Cras TA, Spitzmiller RE, Albertine KH, Greenberg, JM, Whitsett JA, Akeson AL. VEGF causes pulmonary hemorrage, hemosiderosis and air space enlargement in neonatal mice. Am J Physiol Lung Cell Mol Physiol 287:L134-142, 2004.
Ihida-Stansbury K, McKean DM, Gebb SA, Martin JF, Stevens T, Nemenoff R, Akeson A, Vaughn J, Jones PL. Pair-related homeobox gene Prx1 is required for pulmonary vascular development. Circulation Research 94:1507-1514, 2004.
Greenberg JM, Thompson FY, Brooks SK, Shannon JM, Akeson AL. Slit and Robo Expression in the Developing Mouse Lung. Dev Dynamics 230:350-360, 2004.
Akeson AL, Cameron JE, Le Cras TD, Whitsett JA, Greenberg JM. VEGF-A induces prenatal neovascularization and alters bronchial development in mice. Pediatric Research, 57:82-88, 2005.
Mallory BP, Mead TJ, Wiginton DAF, Kulkarni RM, Greenberg JM, Akeson AL. Lymphangiogenesis in the developing lung promoted by VEGF-A. Micro vascular Research 72:62-73, 2006.
Contact Dr. Akeson
Dr. Ann L. Akeson, PhD
Division of Pulmonary Biology
MLC7009
Cincinnati Children's Hospital Medical Center
3333 Burnet Ave
Cincinnati, OH 45229
Ann.Akeson@cchmc.org
Phone 513-636-3599
Fax 513-636-7868
