Biomechanics: How Physical Forces Shape Healing and Fibrosis
Visual Elements:
- Left: Artery/fibroblast under mechanical stress (animated arrows).
- Right: Graph of "Stress-Strain Curve" in healthy vs. fibrotic tissue.
Key Points:
Definition:
Biomechanics = Study of how forces (tension, shear, stiffness) affect living tissues.
Key Players:
- ECM Stiffness: Fibrotic tissue is 10x stiffer than normal.
- Cellular Sensors: Integrins, YAP/TAZ, mechanosensitive ion channels.
Disease Links:
- Fibrosis: Stiff matrix → Activates myofibroblasts → More collagen.
- Atherosclerosis: Shear stress alters endothelial cell behavior.
Speaker Notes
"Biomechanics isn't just about physics—it's a language cells use to communicate. Here's how it works:
- In a healthy heart, flexible ECM allows normal contraction. But after infarction, stiff scar tissue forces cardiomyocytes to work harder, leading to failure.
- Fibroblasts sense stiffness via integrins, activating YAP/TAZ—a pro-fibrotic switch. This creates a vicious cycle: fibrosis begets more fibrosis.
- In blood vessels, low shear stress (e.g., at bifurcations) promotes atherosclerosis by triggering endothelial inflammation.
Clinical Example:
- Liver stiffness (measured by FibroScan) predicts cirrhosis progression.
- Therapeutic angle: Drugs targeting YAP/TAZ (e.g., verteporfin) are in trials for fibrosis.
Optional Add-On Slides
How to Measure Biomechanics:
Atomic force microscopy, traction force microscopy.
Therapeutic Targets:
LOXL2 inhibitors (e.g., simtuzumab) for ECM crosslinking.
Let me know if you'd like these expanded!
Shear Stress and Atherosclerosis: Key Mechanisms
1. Low Shear Stress (LSS) Promotes Atherosclerosis
Location:
Occurs at arterial bifurcations (e.g., carotid sinus, coronary bifurcations) and inner curvatures (e.g., aortic arch).
Mechanisms:
Endothelial Dysfunction:
- ↓ eNOS activity → Reduced NO production → Vasoconstriction, inflammation.
- ↑ ROS (NADPH oxidase-driven) → Oxidative stress.
Pro-Inflammatory Signaling:
- ↑ NF-κB → Increases adhesion molecules (VCAM-1, ICAM-1) → Monocyte recruitment.
- ↑ TLR4/MyD88 pathway → Promotes cytokine release (IL-6, TNF-α).
Plaque-Prone Phenotype:
- ↑ LDL retention (due to disturbed flow).
- ↑ Macrophage infiltration → Foam cell formation.
2. High Shear Stress (HSS) is Protective
Location:
Found in straight arterial segments (e.g., mid-left anterior descending artery).
Mechanisms:
Endothelial Quiescence:
- ↑ eNOS/NO → Anti-inflammatory, vasodilatory.
- ↑ Kruppel-like factor 2 (KLF2) → Suppresses NF-κB.
Anti-Atherogenic Effects:
- ↓ LDL retention (laminar flow clears lipids).
- ↑ Autophagy → Clears damaged organelles.
3. Clinical Evidence
Imaging Studies:
- 4D Flow MRI shows plaque develops in low-shear regions.
- OCT/IVUS: Thin-cap fibroatheromas (vulnerable plaques) correlate with LSS.
Animal Models:
ApoE⁻/⁻ mice with induced LSS develop plaques at bifurcations.
4. Therapeutic Implications
Drugs Targeting Shear-Sensitive Pathways:
- Statins ↑ eNOS/NO.
- SGLT2 inhibitors (empagliflozin) ↑ KLF2.
Endothelial Mechanomodulation:
- Stent design to restore laminar flow.
- Exercise ↑ shear stress → Improves endothelial function.
5. Summary
| Shear Stress Type | Effect on Endothelium | Atherosclerosis Risk |
|---|---|---|
| Low (Disturbed) | Inflammatory, Dysfunctional | High (Plaque formation) |
| High (Laminar) | Protective, Quiescent | Low (Plaque resistance) |
Key Takeaway
- Low shear stress drives atherosclerosis via inflammation, LDL retention, and endothelial dysfunction.
- High shear stress is protective but can erode plaques if flow is turbulent.