NEW APPROACH TO ENDOTHELIAL CLEFT STRUCTURE

  • Curry, Fitz-Roy E, (PI)

Project: Research project

Description

The overall aim of our research is to develop a combined engineering,
ultrastructural and biophysical approach to the mechanisms whereby
endothelial cells and the clefts between the cells modulate microvessel
permeability. Freeze fracture studies and ultrathin serial sections have
demonstrated that endothelial cells are joined by an array of junctional
strands which are interrupted at intervals allowing passage of water and
solutes. Cytochemical and permeability studies also indicate that all or
part of the cleft may be filled with a fibrous matrix. We describe novel
experiments guided by a new conceptual theoretical framework to relate
permeability properties of segments of individually perfused microvessels,
having known permeability properties, to the ultrastructure of the
junctional strands between adjacent endothelial cells and a fiber matrix
within the cleft. The specific aims of the proposal are 1) to evaluate the
proposal that the permeability properties of microvessel walls to water and
small solutes are determined by the frequency of small discontinuities in
the junctional strand; and 2) to evaluate the relative contribution of
structures associated with the junctional strand and the fiber matrix to
the molecular filter at the microvessel wall. The primary focus of our new
approach is the analysis of the three-dimensional convective-diffusive
spread of tracer molecules on the albuminal side of the interruptions in
the junction strand arrays. This spread is analogous to the growth of a
wake on the downstream side of a small object at very low Reynolds numbers.
Preliminary results from serial sections by Dr. Adamson indicate that this
approach is necessary to investigate the geometry and distribution of
hypothetical small pores or slits in the junction strands which cannot be
resolved by conventional 30-40nm sections. The combined theoretical and
experimental approach adopted herein takes advantage of a recently
developed highly accurate analytic solution by Dr. Weinbaum for the
three-dimensional viscous flow in a cleft, which contains junction strands
with discrete pores and slender cross-bridging fiber components. The model
is needed to interpret the three-dimensional distribution of tracer in the
wake experiments proposed in Specific Aim 1, and to analyze the results of
the experiments with larger solute molecules proposed in Specific Aim 2.
In both experimental designs measurements will be performed on individual
perfused microvessels of precisely known permeability properties using
techniques that have been extensively developed in Dr. Curry's laboratory.
We believe this combined theoretical and experimental approach goes far
beyond past and current attempts to delineate the junction and fiber matrix
structures which modulate microvessel permeability. These studies are the
most direct approach to a new understanding of the nature of the
resistances which determine microvessel permeability in normal tissue and
during recovery from injury.
StatusFinished
Effective start/end date5/1/913/31/12

Funding

  • National Institutes of Health: $448,341.00
  • National Institutes of Health
  • National Institutes of Health: $459,126.00
  • National Institutes of Health: $434,036.00
  • National Institutes of Health
  • National Institutes of Health: $450,694.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $413,527.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $435,867.00
  • National Institutes of Health: $435,091.00
  • National Institutes of Health
  • National Institutes of Health: $449,579.00
  • National Institutes of Health: $438,995.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health

Fingerprint

permeability
solutes
strands
endothelial cells
shear stress
tracer techniques
osmotic pressure
sieves
water
tracers
fibers
Sturnidae
crack bridging
porosity
sieving
interruption
colloids
low Reynolds number
viscous flow
matrices

Keywords

  • Medicine(all)