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Lecture 3

PATH 310 Lecture Notes - Lecture 3: Low-Density Lipoprotein, Nfe2L2, Shear Stress


Department
Pathology and Molecular Medicine
Course Code
PATH 310
Professor
Christine Hough
Lecture
3

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ATHEROSCLEROSIS
A complex disease heavily influenced by environmental factors
Disease of elastic and muscular arteries (large to medium sized vessels)
Lose of arterial elasticity Vessel thickening and stiffening
* The plasma of individuals with atherosclerosis is very milky due to elevated lipids
(LDL cholesterol bad fat)
* Architecture of arteries can also lead to atherosclerosis, which doesn’t depend on
ones diet but is genetic. These individuals are prone to develop atherosclerosis
ATHEROMATOUS PLAQUE
- The first lesion is called the fatty streak
- The development of the lesion occurs between the endothelial cells and the smooth
muscle cells
* It is characterized by a build-up of lipids, cholesterol, calcium, and cellular debris
- As the plaque gets bigger it hardens and starts to occlude the lumen
- This limits blood flow and tissues downstream don’t get enough oxygen ischemia
- The plaque can rupture and lead to a very large thrombosis
* Plaques can lead to endothelial dysfunction and vascular inflammation
NORMAL BLOOD VESSELS
Consist of 3 concentric layers
1) Tunica Intima
A. Endothelial Cells
B. Subendothelial Matrix (contains VWF)
2) Tunica Media
A. Smooth Muscle Cells (express TF)
B. Elastin
3) Tunica Adventitia
A. Connective Tissue (collagen fibers)
DIFFERENCE BETWEEN ARTERIES AND VEINS
Arteries
- The tunica media is much thicker
- The vessels compensate for high blood pressure and blood flow
* Atherosclerosis forms at atherosclerotic prone regions
- Bifurcations, Branch sites, Curves
- Aorta, Carotid, Coronary, Renal, and arteries of the lower extremities
** The aortic arch is where there are many bifurcations and is a big area of
concern
Veins
- Have valves
- The vessels have thin non-elastic walls
* Thrombis forms before the valves where the blood is relatively still
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MECHANICAL FORCES ON VESSEL WALL
Pressure: Is normal to the wall and results in stretching of the vessel wall SM cells
Shear stress: Is parallel to the wall and is exerted longitudinally in the direction of
blood flow Endothelial cells
SHEAR STRESS
1. Results from the flow of viscous blood and effects endothelial cell function
Endothelial cells prefer laminar flow
Turbulent and oscillatory flow can lead to endothelial dysfunction
They create low levels of shear stress
2. There are different levels and types of shear stress
A. The magnitude of shear stress is…
i. Directly proportional to blood flow and fluid viscosity
ii. Inversely proportional to vessel radius
B. High shear stress..
ii. Is due to high flow and small lumens
ii. Low flow and large lumen causes low shear stress
C. Veins have a low range of shear stress while arteries have a high range of
shear stress
3. It can cause difference in endothelial phenotype
- Endothelial cells have the ability to take physical stress and convert it into
biochemical signals
- This mechanosensory complex at the endothelial cell-cell junction activates…
PECAM-1, VE-cadherin, VEGFR2
* It is through kinase phosphorylation that the complex is activated
NFkB: Is a transcription factor that turns
on proimflammatory cytokines and
chemoreceptors
KLF2, Nrf2: Are transcription factors that
inhibit NFkB to prevent the activation of
proimflammatory cytokines
Master regulators, KLF2 and Nrf2…
KLF2: Inhibit vascular tone, thrombosis and promote intercellular communication
Nrf2: Inhibit oxidative stress
KLF2, Nrf2: Work collectively to inhibit inflammation
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