Vascular Remodeling of the Blood Brain Barrier
2011-01
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Vascular Remodeling of the Blood Brain Barrier
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2011-01
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Abstract
The human brain contains a vast network of blood vessels, capillaries, and
microvessels. The blood brain barrier (BBB) is made up of three main components:
resident endothelial cells (ECs), tight junctions, and a basement membrane. This barrier
is impermeable to most solutes, bacteria, antibodies, chemicals, and drugs. It does,
however, allow for the transport and diffusion of substances that are metabolically
necessary in the brain such as glucose and oxygen. The transport of glucose is
facilitated by Glut-1, a brain endothelial cell specific glucose transporter. The loss or
deficiency of Glut-1 in the BBB has been clinically diagnosed in humans. Glut-1
deficiency syndrome is characterized by a haploinsufficiency of the wild type Glut-1;
the dominant non-functional mutation causes the clinical manifestations related to the
syndrome. The manifestations begin in infancy and, if undiagnosed, may cause serious
developmental delay, acquired microcephaly, seizures, ataxia, and spasticity. The only
known treatment is a ketogenic diet which eliminates the brain’s need for glucose in
metabolism. Incorporation of genetically engineered ECs or endothelial progenitor cells
(EPCs) that contain the gene for the wild type Glut-1 into the brain vasculature would
correct this syndrome in addition to opening the door for treating other CNS diseases.
The proposed mechanism for incorporating new cells into the BBB is via postnatal
neovasculogenesis. Postnatal neovasculogenesis occurs in ischemia, hypoxia, and
tumor growth. There are two modes of postnatal neovasculogenesis: angiogenesis and
vasculogenesis. Angiogenesis is the process by which the resident ECs proliferate
when the signal for growth of new vessels is received. Theoretically, during the process
of vasculogenesis EPCs are recruited from the bone marrow, differentiate, proliferate,
and migrate to the signaling tissue and incorporate into the new vessel. My research
project focused on method development to incorporate cells into the brain
neovasculature. I focused this development further to incorporation of cultured and
bone marrow-derived ECs and EPCs into the neovasculature through hypoxia-mediated
outgrowth or BBB disruption.
We have now developed a method for investigating the effects of hypoxia on
vascular remodeling and EPC and EC recruitment into the neovasculature. In this
method we utilized two models; direct injection of cultured ECs and EPCs into the brain
followed by hypoxia, or osmotic disruption of the BBB followed by injection of ECs
and EPCs. Cultured ECs were isolated from brain microvessels. Cultured human EPCs
were isolated from peripheral blood. ECs and EPCs display different antigens that allow
for immunohistochemical detection. The different combinations of antigens elucidate
the different cell types. ECs display antigens for Glut-1, CD31, and von Willebrand
Factor. Bone marrow-derived EPCs display antigens for CD31 and Tie2, but do not
display antigens for von Willebrand Factor. Immunohistochemistry was used to
characterize the cells as EPCs or ECs prior to injection and determine location of the
cells in the brain after animals are exposed to hypoxia using the specific antigens for
ECs and EPCs.
Description
University of Minnesota Master of Science thesis. January 2011. Major: Chemistry. Advisor: Grant W. Anderson. 1 computer file (PDF); vii, 59 pages.
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Johnson, Arial Raina Larson. (2011). Vascular Remodeling of the Blood Brain Barrier. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/104177.
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