An Apoptotic Failsafe Program Involving PDGF-dependent PI 3- Kinase Activity Contributes to Plaque Composition in Atherosclerosis
Year: 2026
Type: preprint
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 β (PDGFRβ) 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 PDGFRβ 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 PDGFRβ (PDGFRβ- F2/F2) reduced VSMC apoptosis in plaques as well as in cultured VSMCs. Further analyses revealed that PI3K isoform p110α mediates VSMC survival, whereas p110δ and p110β rather promote apoptosis. We identified a pro-apoptotic PDGFRβ-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 H 2 O 2 or Fas ligand. Consistently, Bcl-2 expression was elevated in plaques from PDGFRβ-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.
Institutions: University of Cologne, University Hospital Cologne, University Hospital Ulm, Universitätsmedizin Göttingen, German Centre for Cardiovascular Research, Düsseldorf University Hospital, Heinrich Heine University Düsseldorf, University of Hawaiʻi at Mānoa, University of Hawaii System, The University of Texas Southwestern Medical Center
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
Funder: Deutsche Forschungsgemeinschaft
OpenAlex ID: W7224134771