An Apoptotic Failsafe Program Involving PDGF-dependent PI 3-Kinase Activity Contributes to Plaque Composition in Atherosclerosis

Vantler, M.; Berghausen, E. M.; Schwab, M. M.; Zierden, M.; Zimmermann, W.-H.; Gerdes, N.; Tallquist, M. V.; Herz, J.; Winkels, H.; Baldus, S.; Rosenkranz, S.

doi:10.64898/2026.10.26.761862

bioRxiv · 10.64898/2026.10.26.761862

An Apoptotic Failsafe Program Involving PDGF-dependent PI 3-Kinase Activity Contributes to Plaque Composition in Atherosclerosis

Vantler, M.·Berghausen, E. M.·Schwab, M. M.·Zierden, M.·Zimmermann, W.-H.·Gerdes, N.·Tallquist, M. V.·Herz, J.·Winkels, H.·Baldus, S.·Rosenkranz, S.

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Abstract

Background: Growth and stability of atherosclerotic plaques are impacted by vascular smooth muscle cell (VSMC) apoptosis which is believed to be suppressed by growth factor dependent activation of phosphoinositide 3-kinase (PI3K). Here, we analyzed the effects of chronically elevated platelet-derived growth factor receptor {beta} (PDGFR{beta}) signaling on VSMC apoptosis and aortic plaque composition during atherogenesis. Methods: We assessed atherosclerosis in low-density lipoprotein receptor deficient mice, lacking low-density lipoprotein receptor-related protein 1 in VSMCs (LDLR-/-smLRP1-/- mice), in that smLRP1 deficiency resulted in PDGFRB overexpression. Apoptosis and downstream signaling was investigated in cultured aortic VSMCs. Results: Chronically elevated PDGFR{beta} signaling in LDLR-/-smLRP1-/- mice unexpectedly increased VSMC apoptosis in atherosclerotic plaques. In vitro, PDGF exerted transient anti-apoptotic effects on VSMCs, whereas long-term stimulation promoted cell death. Mutation of the PI3K binding site in the PDGFR{beta} (PDGFR{beta}-F2/F2) reduced VSMC apoptosis in plaques as well as in cultured VSMCs. Further analyses revealed that PI3K isoform p110 mediates VSMC survival, whereas p110{delta} and p110{beta} rather promote apoptosis. We identified a pro-apoptotic PDGFR{beta}-driven signaling pathway in VSMCs involving PI3K-dependent induction of c-Myc that in turn suppresses the expression of anti-apoptotic Bcl-2. PDGF-dependent downregulation of Bcl-2 increases the susceptibility of VSMCs to apoptotic agonists like H2O2 or Fas ligand. Consistently, Bcl-2 expression was elevated in plaques from PDGFR{beta}-F2/F2 mice. Conclusions: Our study expands the understanding of the role of growth factors in regulating apoptosis and argues against their role as pure survival factors. This has direct implications in atherogenesis, as chronically elevated PDGF does not mediate VSMC survival in atherosclerotic plaques, but rather promotes cell death in the VSMC-rich fibrous cap, thus promoting plaque instability and rupture.

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Vantler, M., Berghausen, E. M., Schwab, M. M., Zierden, M., Zimmermann, W.-H., Gerdes, N., Tallquist, M. V., Herz, J., Winkels, H., Baldus, S., Rosenkranz, S.. 2026-10-28. An Apoptotic Failsafe Program Involving PDGF-dependent PI 3-Kinase Activity Contributes to Plaque Composition in Atherosclerosis. https://doi.org/10.64898/2026.10.26.761862

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