Atherosclerotic Consequences of Disrupted Oxygen Sensing Signaling in Vascular SMCs

• Autores: Raúl Izquierdo Serrano
• Directores de la Tesis: Jacob Fog Bentzon (codir. tes.), Daniel Morales Cano (codir. tes.)
• Lectura: En la Universidad Autónoma de Madrid ( España ) en 2026
• Idioma: inglés
• Títulos paralelos:
  • Consecuencias ateroscleróticas de la disrupción de la señalización de detección de oxígeno en las células del músculo liso vascular
• Tribunal Calificador de la Tesis: Vicente Andrés García (presid.), Julián Aragonés López (secret.), Mandy Grootaert (voc.)
• Programa de doctorado: Programa de Doctorado en Biociencias Moleculares por la Universidad Autónoma de Madrid
• Menciones:
  • Internacional
• Calificación: Sobresaliente Cum Laude
• Materias:
  • Ciencias médicas
    • Patología
      • Arterioesclerosis
• Enlaces
  • Tesis en acceso abierto en: Biblos-e Archivo
• Resumen

  • Atherosclerotic plaques suffer from low oxygen (hypoxic enviroment). While hypoxia-HIF signaling has been studied in macrophages and endothelial cells, how it shapes smooth muscle cell (SMC) behavior and phenotypic switching remains unclear despite SMCs being a major plaque constituent. This thesis investigated how SMC-intrinsic HIF activity influences SMC behavior, plaque structure, and systemic outcomes.

    First aim (SMC Hif1a loss-of-function). Using tamoxifen-inducible Myh11-CreERT2 in a mouse model of established atherosclerosis (rAAV-PCSK9 and high-fat diet), we conditionally deleted Hif1a in SMCs to impair hypoxia sensing. HIF1α loss yielded larger lesions with expanded necrotic cores and increased calcification, alongside expanded apoptosis. Notably, immunofluorescence studies showed a selective expansion of SMC-derived states with chondromyocyte-like features. Additionally, single-cell profiling of lineage-traced cells showed reduced OXPHOS together with increased stress/proteostasis programs. Complementary in vitro experiments silencing Hif1a confirmed activation of oxidative stress responses with higher reactive oxygen species (ROS) production, aligning with the in vivo findings. Together, these data support that SMC HIF1α functions as a metabolic safeguard in advanced plaques: hypoxia is the dominant stressor, whereas HIF1α activity is an adaptive response that limits cell loss and mineralization; blocking it worsens pathology.

    Second aim (SMC Vhl loss-of-function). To model constitutive HIF activation, we deleted Vhl in SMCs during atherogenesis. VhlSMC-KO redirected SMCs away from a chondroid programs toward hypoxia-adapted, remodeling states and engaged an angiocrine signature within plaques. Systemically, Vhl deletion provoked erythrocytosis and cardiomegaly and dampened late-phase weight gain and plasma cholesterol exposure. Genetic dissection with double knockouts separated the axes: HIF2α proved indispensable for the erythropoietic/systemic effect, as its removal normalized hematocrit and restored classic murine plaque features, whereas HIF1α was dispensable for the atypical architecture but required for metabolic tolerance and survival in the Vhl background.

    Conclusion. In SMCs, HIF signaling can push disease in two directions: loss of HIF1α activity makes plaques metabolically fragile and worse, whereas excessive HIF activity (via Vhl loss) triggers systemic EPO effects. These results support isoform-aware strategies: reduce hypoxia and maintain protective HIF1α signaling in SMCs, while controlling the HIF2α-EPO/hematocrit axis to limit systemic burden.