- Paper Report
- Open Access
Implications of angiogenic heterogeneity
- Oliver Distler1
© Current Science Ltd 2000
- Published: 9 May 2000
In physiologic conditions, vascular endothelial cells rarely proliferate but remain differentiated and quiescent. This quiescence is the result of low levels of endothelial cell growth stimulators and high basal levels of inhibitors. In pathologic conditions, this stimulator to inhibitor ratio is disturbed by either favoring angiostatic factors (disorders with decreased angiogenesis, such as systemic sclerosis) or endothelial growth stimulators (disorders with enhanced angiogenesis, such as RA). To determine whether this angiogenic balance is genetically determined.
Compared to C57BL/6J mice, 3/16 strains of mice had a significantly lower angiogenic response in the corneal micropocket assay when 80 ng bFGF was applied. A significant increase in neovascularization relative to that for C57BL/6J mice was observed in 15/21 strains when 10 ng bFGF was applied. Analysis of vessel growth at different doses of bFGF revealed that the induced neovascularization area was linearly related to the amount of bFGF, with a maximum of 0.25 mm/day at 80 ng in C57BL/6J mice. In contrast, the SJL/J strain reached a plateau at 0.15 mm/day for doses above 10 ng. As an example of strains with a high angiogenic susceptibility, 129/SvImJ mice produced a near maximal response of 0.25 mm/day with bFGF doses of only 10 ng. Interestingly, formation of hyphemas (as one marker of iris neovascularization) was found significantly more often in albino strains than in their related pigmented strain, indicating that factors linked to pigmentation/melanin produced an inhibitory influence on the angiogenic balance. Differences in the sensitivity between the 129 and C57BL/6J strains similar to the differences found for the bFGF experiments were found with VEGF induced corneal neovascularization. In line with the stimulation experiments, treatment with angiogenesis inhibitors resulted in an enhanced level of inhibition in 129/ReJ (high angiogenic susceptibility) and a lack of inhibition in SJL/J mice. In vitro, aortic ring outgrowth of endothelial cells was significantly higher for samples from 129/ReJ mice than for C57BL/6J or SJL/J mice. The addition of growth factors (including bFGF and VEGF) caused a marked increase in endothelial sprouting from both the C57BL/6J and 129/SvImJ but not the SJL/J mice, similar to the blunted response in the corneal assay.
Inbred strains of mice were examined for their vascular responsiveness using the cornea micropocket assay. Sucralfate pellets containing various concentrations of basic fibroblast growth-factor (bFGF) or vascular endothelial growth factor (VEGF) were implanted into the corneal stroma. The induced vascular response was assessed measuring the maximal vessel length and clock hours of neovascularization. The sensitivity to angiogenesis inhibitors was determined by injections of TNP-470 and thalidomide. For in vitro studies, the endothelial outgrowth from aortic rings taken from different mouse strains was assessed in the aortic ring assay with and without growth factor supplements.