The key players of the hypoxic response are the
hypoxia-inducible factors (Hif), whose α-subunits are tightly regulated by Prolyl-4-hydroxylases (PHD), predominantly by PHD2. Monocytes/Macrophages are involved in
atherosclerosis but also restenosis and were found at hypoxic and sites of the lesion. Little is known about the role of the myeloid PHD2 in
atherosclerosis and
neointima formation. The study aimed to investigate the consequences of a myeloid deficiency of PHD2 in the process of
neointima formation using an arterial denudation model. LysM-cre mice were crossed with PHD2fl/fl, PHD2fl/fl/Hif1αfl/fl and PHD2fl/fl/Hif2αfl/fl to get myeloid specific knockout of PHD2 and the Hif-α subunits. Denudation of the femoral artery was performed and animals were fed a western type diet afterwards with analysis of
neointima formation 5 and 35 days after denudation. Increased
neointima formation in myeloid PHD2 knockouts was observed, which was blunted by double-knockout of PHD2 and Hif1α whereas double knockout of PHD2 and Hif-2α showed comparable lesions to the PHD2 knockouts. Macrophage infiltration was comparable to the
neointima formation, suggesting a more inflammatory reaction, and was accompanied by increased intimal
VEGF-A expression.
Collagen-content inversely correlated to the extent of
neointima formation suggesting a destabilization of the plaque. This effect might be triggered by macrophage polarization. Therefore, in vitro results showed a distinct expression pattern in differentially polarized macrophages with high expression of Hif-1α,
VEGF and MMP-1 in proinflammatory M1 macrophages. In conclusion, the results show that myeloid Hif-1α is involved in
neointima hyperplasia. Our in vivo and in vitro data reveal a central role for this
transcription factor in driving plaque-vascularization accompanied by matrix-degradation leading to plaque destabilization.