Background: Neovascularisation of the vasa vasorum (VV) is noted in the early
stage of atherosclerosis; however, its pathophysiological role remains unclear.
Proteasome inhibition has been shown to yield anti-angiogenic effects and to
induce and aggravate atherosclerosis in normal (N) and hypercholesterolemic
(HC) pigs.
Purpose: To test the hypothesis that early atherogenesis develops without concomitant
VV neovascularization in the setting of proteasome inhibitor treatment.
Methods: Female pigs (n=4 per group) were randomized to either N or HC group
without or with additional treatment of the proteasome inhibitor MLN-273 (0.08
mg/kg SQ twice weekly, N+PSI or HC+PSI). The coronary arteries were harvested
after twelve weeks and processed for micro-CT imaging and tissue analyses.
Results: As presented in the table, compared with N, VV density was increased
in HC but not N+PSI or HC+PSI (2.8±0.2 vs. 5.0±0.9, 2.5±0.8, and 2.1±0.1
n/mm2, p<0.05; figure) as was vascular-area-fraction (0.64±0.13 vs. 1.80±0.34,
0.68±0.21, and 0.60±0.07%, p<0.01). Compared with N, the percentage of Ki-
67-positive VV tended to be higher in HC but not in N+PSI or HC+PSI (5.0±1.4
vs. 16.4±4.2, 13.9±9.2, and 1.0±0.4%, p<0.01). HIF-1α expression in the outer
media, compared with N, was higher in HC, N+PSI, and HC+PSI (45.0±3.1 vs.
65.9±3.3, 74.8±4.7, and 77.8±3.0%, p<0.01 for HC vs. HC+PSI). VEGF staining
per field in the adventitia, compared to N, was increased in HC, but not in N+PSI
and HC+PSI (7.08±2.14 vs. 24.76±4.34, 2.52±1.70, and 1.03±0.54%, p<0.01).
Conclusions: The current study shows that chronic proteasome inhibition prevents
the increase in VV density in HC pigs but does not cause a significant decrease
in VV density in N pigs. The underlying pharmaceutical mechanism seems
to include the HIF-1α-VEGF-pathway.
As chronic proteasome inhibition was shown before to induce and aggravate
atherosclerosis in N and HC pigs, the current findings would suggest that the
early stage of atherosclerosis did not necessarily require VV neovascularization
for its development.
Acknowledgement/Funding: National Institutes of Health grants; Mayo Foundation;
Mayo Stiftung