Clinical Interests
Not applicable

Research Interests

We are interested in the molecular controls that govern blood vessel formation. We study how blood vessels are formed during mouse development because it is fascinating, and because many molecular processes used during embryonic blood vessel formation are reused when blood vessels are formed inappropriately by a solid tumor. Tumor angiogenesis is one important factor in the growth and spread of cancer as well as one that is increasingly a target of new cancer therapies. One aspect of our work uses a model in which mouse embryonic stem cells differentiate in the incubator to form several cell types. Because they form blood vessels in this model, we can use it to study the early processes that lead to the formation of new blood vessels. Our recent work has used this model to study aspects of a particular signaling pathway that is important in blood vessel formation. The signal in this pathway is called VEGF (vascular endothelial growth factor) and one receptor is called flt-1 or VEGFR-1. We obtained stem cells with a targeted mutation in either VEGF or the receptor. We found that the mutations resulted in opposite phenotypes - the lack of VEGF prevented differentiation of stem-cell derived blood vessels, while lack of the receptor resulted in overproduction of stem-cell derived blood vessels. This data supported a model in which the VEGFR-1 receptor normally acts to negatively regulate blood vessel formation, and we showed that it does so by controlling the rate of proliferation of blood vessel cells. This finding suggests several potential targets to control blood vessel formation in the clinic.

The stem cell model is also being used to image the formation of blood vessels. The green fluorescent protein (GFP) gene was linked to promoters expressed in vascular cells, and put into stem cells. Upon differentiation, the vascular cells express GFP and can be followed over time. We have used time-lapse imaging to generate movies of blood vessel formation, and we now can see for the first time the actual cellular processes that contribute to forming blood vessels. We recently extended these observations to investigation of dynamic processes in vessels mutant for the VEGF receptor flt-1. We showed that, in addition to the proliferation defect described above, the flt-1 mutant vessels had a defect in angiogenic sprouting. These results indicate that the flt-1 VEGF receptor impacts on multiple signaling pathways important in blood vessel formation.

We also study the process of vascular pattern formation, in other words how the blood vessels know where to form. This is a critical parameter of both embryonic and tumor-driven blood vessel formation that is just now amenable to dissection experimentally. We have developed a unique mouse-avian chimeric embryo model to study patterning, since the process is not properly reproduced during stem cell differentiation. This process takes portions of mouse embryos and places them into a bird embryo from which the same tissue is removed. Because we can mark the graft mouse cells, we can follow where the blood vessels migrate from the graft into the bird host. We found that the vascular cells from the mouse grafts in general obey the vascular patterning cues in the bird host environment. The mouse cells migrate from the graft site, sometimes over long distances in embryonic terms, and contribute to blood vessel formation by forming either mouse vessels, large patches of mouse vessel in bird vessels, or even finely interdigitated mouse and bird cells to form a blood vessel. We have also identified two embryonic structures as the source of vascular patterning signals by transplant analysis: the neural tube is the source of a positive signal, and the notochord, a structure that will help form the backbone, is the source of a negative patterning signal. We recently showed that VEGF-A is a critical component of the neural tube-derived vascular patterning signal.

Recent Accomplishments and Honors
Charter Member, NIH Pathology A Study Section

Member, American Heart Association Cardiovascular Study Section, Mid-Atlantic

Councilor, North American Vascular Biology Organization (NAVBO) [elected position]

Invited Speaker, Gordon Research Conference on Angiogenesis and Microcirculation, 2003

We identified a neural tube derived vascular patterning signal in 2004 using novel mouse-avian chimera and explant analysis - this finding helps understand how vessels migrate, which is important for tumor angiogenesis

We showed that the VEGF receptor flt-1 negatively modulates cell division but positively modulates vascular sprout formation using fixed point and dynamic image analysis in 2004- this finding shows the complex role of VEGF signaling in blood vessel formation, and indicates that therapeutic targets must be chosen wisely

Training
Victoria Bautch received her PhD from the University of Illinois Chicago, where she studied Drosophila muscle development with Dr. Bob Storti, and identified the first cytplasmic tropomyosin in flies. She did post-doctoral work with Dr. Doug Hanahan at Cold Spring Harbor Laboratory, where she studied the tumor-promoting effects of viral oncogenes in transgenic mice, and first showed that polyomavirus Middle T promotes hemangioma formation.

Publications
Roberts, D.M., Anderson, A.L., Hidaka, M., Swetenburg, R.L., Patterson, C., Stanford, W.L., and Bautch, V.L. (2004). A vascular gene trap screen defines RasGRP3 as an angiogenesis-regulated gene required for the endothelial response to phorbol esters. Mol. Cell. Biol. (In press).

Hogan, K.A., and Bautch, V.L. (2004). Blood vessel patterning at the embryonic midline. Curr. Topics Dev. Biol. 62, 55-85.

Kearney, J.B.*, Kappas, N.C.*, Ellerstrom, C., DiPaola, F.W., and Bautch, V.L. (2004). The VEGF receptor flt-1 (VEGFR-1) is a positive modulator of vascular sprout formation and branching morphogenesis. Blood 103, 4527-4535 (*= co-first authors).

Hogan, K.A.*, Ambler, C.A.*, Chapman, D.L., and Bautch, V.L. (2004). The neural tube patterns vessels developmentally using the VEGF signaling pathway. Development 131, 1503-1513 (*= co-first authors).

Roberts, D., Kearney, J.B., Johnson, J.H., Rosenberg, M.P., Kumar, R., and Bautch, V.L. (2004). The VEGF receptor flt-1 (VEGFR-1) modulates flk-1 (VEGFR-2) signaling during blood vessel formation. Am. J. Path. 164, 1531-1535.

Bautch, V.L., and Ambler, C.A. (2004). Assembly and patterning of vertebrate blood vessels. Trends Cardiovasc. Med. 14, 138-143.

Kearney, J.B., and Bautch, V.L. (2003). In vitro differentiation of mouse ES cells: hematopoietic and vascular development. In Meth. Enzymol. vol. 365, Differentiation of Embryonic Stem Cells (eds. P.M. Wassarman and G.M Keller), pp. 83-98, San Deigo CA: Elsevier Academic Press.

Ambler, C.A., Schmunk, G.M., and Bautch, V.L. (2003). Stem cell-derived endothelial cells/progenitors migrate and pattern in the embryo using the VEGF signaling pathway. Dev Biol 257, 205-19.

Kearney, J.B., Ambler, C.A., Monaco, K.A., Johnson, N., Rapoport, R.G., and Bautch, V.L. (2002). Vascular endothelial growth factor receptor Flt-1 negatively regulates developmental blood vessel formation by modulating endothelial cell division. Blood 99, 2397-2407. [cover photo]

Bautch, V.L. (2002). Embryonic stem cell differentiation and the vascular lineage. Methods Mol Biol. 185, 117-125.

Ambler, C.A., Nowicki, J.L., Burke, A.C., and Bautch V.L. (2001). Assembly of trunk and limb blood vessels involves extensive migration and vasculogenesis of somite-derived angioblasts. Dev Biol. 234, 352-364.

Bautch, V.L., Redick, S.D., Scalia, A., Harmaty, M., Carmeliet, P., and Rapoport, R. (2000). Characterization of the vasculogenic block in the absence of vascular endothelial growth factor-A. Blood 95, 1979-1987.

E-mail: bautch@med.unc.edu
Telephone: (919) 966-6797
FAX: (919) 962-8472
Address: 502 Fordham Hall 048 Chapel Hill, NC
URL: www.unc.edu/~vbautch/index.htm
Click below for more information in PDF format: /research/faculty/pdf/bautch.pdf

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