PI 3-kinase isoform p110α controls smooth muscle cell functionality and protects against aortic aneurysm formation

bioRxiv (Cold Spring Harbor Laboratory)

Abstract

Abstract Background Catalytic class IA PI 3-kinase isoform p110α is a crucial regulator of cellular proliferation and survival in numerous cell types. While p110α is critically involved in pathogenic vascular remodeling, its physiological role for vascular integrity under stress conditions has not been studied. We report a protective function of smooth muscle p110α against abdominal aortic aneurysm (AAA) formation. Methods & Results In mice lacking p110α in smooth muscle cells (sm-p110α -/- ), perfusion of the infrarenal aorta with porcine pancreatic elastase (PPE) yielded substantially enhanced AAA formation compared to wild type controls. This disease phenotype is partly attributable to a subtle preexisting vascular phenotype under basal conditions, as sm-p110α -/- mice displayed a smaller media area, deranged aortic wall structure (detached smooth muscle cells, increased apoptotic cell death), and a diminished functional responsiveness of aortic rings to vasodilators. Furthermore, p110α is also implicated in regenerative processes during AAA development: Whereas wild type mice showed increased media hypertrophy, neointima formation and proliferation upon PPE intervention, these vascular remodeling processes were diminished in sm-p110α -/- mice. Concomitantly, increased numbers of elastic fiber breaks and ECM degradation were detected in sm-p110α -/- aorta. Mechanistically, we found that lack of p110α expression impaired smooth muscle cell proliferation, expression of contractile marker genes and production of elastin fibers. This phenotype largely depended on reduced phosphorylation and inactivation of FOXO1, as specific FOXO1 inhibition fully rescued proliferation of p110α -/- smooth muscle cells, and knockdown of FOXO1 increased expression of calponin and elastin. Conclusions Smooth muscle p110α protects against AAA disease by maintaining aortic wall homoeostasis and promoting SMC proliferation to compensate for cell loss during AAA development. Our findings have potential implications for current approaches aimed at p110α inhibition for cancer therapy and suggest new pharmacological strategies to activate p110α signaling in AAA disease.

Authors 17

1. Marius Vantler

   University of Cologne · University Hospital Cologne

   Affiliation as printed

   Center for Molecular Medicine Cologne (CMMC), University of Cologne, Germany

   Clinic III for Internal Medicine (Dept. of Cardiology), Heart Center at the University Hospital Cologne, Cologne, Germany

   Cologne Cardiovascular Research Center (CCRC), Heart Center at the University Hospital Cologne and Medical Faculty, University of Cologne, Germany

2. Maximilian Schorscher

   University of Cologne · University Hospital Cologne

   Affiliation as printed

   Center for Molecular Medicine Cologne (CMMC), University of Cologne, Germany

   Clinic III for Internal Medicine (Dept. of Cardiology), Heart Center at the University Hospital Cologne, Cologne, Germany

   Cologne Cardiovascular Research Center (CCRC), Heart Center at the University Hospital Cologne and Medical Faculty, University of Cologne, Germany

3. Eva Maria Berghausen

   University of Cologne · University Hospital Cologne

   Affiliation as printed

   Center for Molecular Medicine Cologne (CMMC), University of Cologne, Germany

   Clinic III for Internal Medicine (Dept. of Cardiology), Heart Center at the University Hospital Cologne, Cologne, Germany

   Cologne Cardiovascular Research Center (CCRC), Heart Center at the University Hospital Cologne and Medical Faculty, University of Cologne, Germany

4. Joseph B. Moore

   University of Louisville

   Affiliation as printed

   Diabetes and Obesity Center University of Louisville School of Medicine, Louisville, KY

5. Dickson W.L. Wong Aachen Institute of Pathology

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Institute of Pathology, RWTH Aachen University Hospital, Aachen, Germany

6. LI Zhao-long

   Technical University of Munich

   Affiliation as printed

   Department of Vascular and Endovascular Surgery, Technical University Munich, Munich, Germany

7. Max Wißmüller

   University of Cologne · University Hospital Cologne

   Affiliation as printed

   Center for Molecular Medicine Cologne (CMMC), University of Cologne, Germany

   Clinic III for Internal Medicine (Dept. of Cardiology), Heart Center at the University Hospital Cologne, Cologne, Germany

   Cologne Cardiovascular Research Center (CCRC), Heart Center at the University Hospital Cologne and Medical Faculty, University of Cologne, Germany

8. Leoni Gnatzy-Feik

   University of Cologne · University Hospital Cologne

   Affiliation as printed

   Center for Molecular Medicine Cologne (CMMC), University of Cologne, Germany

   Clinic III for Internal Medicine (Dept. of Cardiology), Heart Center at the University Hospital Cologne, Cologne, Germany

   Cologne Cardiovascular Research Center (CCRC), Heart Center at the University Hospital Cologne and Medical Faculty, University of Cologne, Germany

9. Mario Zierden

   University of Cologne · University Hospital Cologne

   Affiliation as printed

   Center for Molecular Medicine Cologne (CMMC), University of Cologne, Germany

   Clinic III for Internal Medicine (Dept. of Cardiology), Heart Center at the University Hospital Cologne, Cologne, Germany

   Cologne Cardiovascular Research Center (CCRC), Heart Center at the University Hospital Cologne and Medical Faculty, University of Cologne, Germany

10. Dennis Mehrkens

    University of Cologne · University Hospital Cologne

    Affiliation as printed

    Clinic III for Internal Medicine (Dept. of Cardiology), Heart Center at the University Hospital Cologne, Cologne, Germany

    Cologne Cardiovascular Research Center (CCRC), Heart Center at the University Hospital Cologne and Medical Faculty, University of Cologne, Germany

11. Matti Adam

    University of Cologne · University Hospital Cologne

    Affiliation as printed

    Clinic III for Internal Medicine (Dept. of Cardiology), Heart Center at the University Hospital Cologne, Cologne, Germany

    Cologne Cardiovascular Research Center (CCRC), Heart Center at the University Hospital Cologne and Medical Faculty, University of Cologne, Germany

12. Margarete Odenthal

    University Hospital Cologne

    Affiliation as printed

    Institute of Pathology, University Hospital Cologne, Cologne, Germany

13. Gerhard Sengle

    University Hospital Cologne

    Affiliation as printed

    Children Hospital, University Hospital Cologne, Cologne, Germany

14. Peter Boor Aachen Institute of Pathology

    Universitätsklinikum Aachen · RWTH Aachen University

    Affiliation as printed

    Institute of Pathology, RWTH Aachen University Hospital, Aachen, Germany

15. Lars Mäegdefessel

    Technical University of Munich

    Affiliation as printed

    Department of Vascular and Endovascular Surgery, Technical University Munich, Munich, Germany

16. Stephan Ernst Baldus

    University of Cologne · University Hospital Cologne

    Affiliation as printed

    Center for Molecular Medicine Cologne (CMMC), University of Cologne, Germany

    Clinic III for Internal Medicine (Dept. of Cardiology), Heart Center at the University Hospital Cologne, Cologne, Germany

    Cologne Cardiovascular Research Center (CCRC), Heart Center at the University Hospital Cologne and Medical Faculty, University of Cologne, Germany

17. Stephan Rosenkranz corresponding

    University of Cologne · University Hospital Cologne

    Affiliation as printed

    Center for Molecular Medicine Cologne (CMMC), University of Cologne, Germany

    Clinic III for Internal Medicine (Dept. of Cardiology), Heart Center at the University Hospital Cologne, Cologne, Germany

    Cologne Cardiovascular Research Center (CCRC), Heart Center at the University Hospital Cologne and Medical Faculty, University of Cologne, Germany