1 / 27

excessive SMC growth within the vascular wall after trauma -proliferation -apoptosis -migration - accelerated matrix de

Intimal hyperplasia. excessive SMC growth within the vascular wall after trauma -proliferation -apoptosis -migration - accelerated matrix deposition major cause of failure of endovascular and vascular reconstructions so far very difficult to treat .

polly
Download Presentation

excessive SMC growth within the vascular wall after trauma -proliferation -apoptosis -migration - accelerated matrix de

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Intimal hyperplasia • excessive SMC growth within the vascular wall after trauma -proliferation -apoptosis -migration - accelerated matrix deposition • major cause of failure of endovascular and vascular reconstructions • so far very difficult to treat

  2. Intimal hyperplasiaaffected by multiple factors • Trauma • Platelet aggregation • Hemodynamic factors • Humoral factors • altered SMC-EC interaction

  3. Intimal hyperplasiaaltered SMC-EC interaction • Endothelially derived -vasodilating agents - relaxation agents vasoconstrictors • Cell to cell interaction?

  4. Intimal hyperplasia in stent -restenosis-

  5. Intimal hyperplasia -restenosis-

  6. Intimal hyperplasia -restenosis management challenging

  7. intimal hyperplasia and EC / SMC interaction are difficult to study • in in vivo studies we cannot separate hemodynamic, intercellular and humoral effects • In in vitro studies cannot reproduce clinical effects of EC/SMC interaction

  8. EC / SMC interaction is difficult to study • In in vivo stable conditions intact confluent ECs control intimal hyperplasia by: -enhanced production of NO -decreased production of endothelin • production of anti inflammatory agents such as heparan sulfate • regenerating ECs may have an opposite effect

  9. in vitro conventional cocultures Endothelial cells • Enhance SMC migration • promote SMC proliferation • encourage unhealthy vascular remodeling • Data from conventional cocultures do not allow direct translation of the results Powell , Cronewett, et al

  10. There is need for in vitro vasculature models • Hemodynamic factors: shear stress, pressure • Matrix • Physiologic features of the vascular wall -compliance, elasticity

  11. EC SMCs Coculture model • Rat aortic SMCs in wells • Rat aortic ECs in inserts • inserts transferred into wells at 24 hrs • semipermeable (3.0mm pore) membrane • no cell contact

  12. Pressure apparatus • Custom-made chamber • 130mm Hg monitored with manometer • 95% room air and 5%CO2 • 370C temperature-humidity • daily media pH measurements

  13. EC SMCs Coculture model Extracellular pressure130-135 mmHg

  14. EC EC SMCs SMCs Four pressure-culture conditions 130mmHg SMCs SMCs 130mmHg

  15. Effect of pressure on EC/SMC coculture C-myc dependent Late entry to S-Phase Vouyouka et al JSR 2003

  16. SMC/0-P SMC/0 SMC/EC-P SMC/EC SMCs stained with TUNEL

  17. Pressure and coculture enhancesSMC apoptosis Topisomerase IIa Fas- Fas Ligand Vouyouka et al Surgery 2004

  18. Effect of pressure and coculture on SMC Topoisomerase II Topo II Actin * 1.6 * 1.2 0.8 0.4 0.0 SMC/0 SMC/EC SMC/0-P SMC/EC-P

  19. Effect of pressure and coculture on SMC Topoisomerase II Topo II Actin * 1.6 * 1.2 0.8 0.4 0.0 SMC/0 SMC/EC SMC/0-P SMC/EC-P

  20. Pressure and coculture increases iNOS *

  21. Extracellular pressure is a major regulator of EC/SMC interaction Regulates cocultured SMC growth by enhancing apoptosis and inhibiting SMC proliferation. Mediates these effects mostly through endothelial paracrine function that involves NO and endothelin mediation

  22. What about vascular wall compliance? Electrospinning fibers with different chemistry and collecting as a single fabric on a rotating mandrel

  23. Project Aims • Synthesize and characterize bioactive PLA scaffolds containing graded layers of variable mechanical compliance, mimicking the compliance of normal and diseased vessels. (Frey) • Investigate endothelial cell and vascular smooth muscle cell adhesion, migration, and proliferation within the stratified layers of the matrices in Aim 1, relating the cell behavior to matrix mechanics. (Reinhart-King) • Adapt the scaffold in Aim 1 to support an endothelial and vascular smooth muscle cell co-culture in different pressure environments to investigate the effect of endothelial cells on vascular smooth muscle cell behavior. (Vouyouka and Reinhart-King)

  24. Future aims • Incorporate to the in vitro vasculature model stents? • try to “treat” the “pathologic” in vitro model with the incorporation -NO bubbles or donors • endothelin receptor antagonists • Hyper cooling of the model • ?????

  25. c-myc actin C-myc levels in SMC cultures P<0.03 Vouyouka et al JSR 2003

  26. Tissue Engineering 3-D architecture Controlled ECM Chemistry Structured mechanical compliance 3D Structured PLA Scaffolds Tissue Replacement Disease Models for Prevention Schematic of our approach to integrate princples of tissue engineering to create a scaffold for models of atherosclerosis and disease. Shaded areas identify novel areas addressed in our project.

More Related