Vascular Endothelial Function & Atherosclerosis

Front 1

What is our protection against atherosclerosis?

Back 1

The endothelium

Front 2

Describe the changes the changes that occur in the intima with the development of atherosclerosis.

Back 2

In a normal vessel the intima is composed of one layer of endothelial cells that are there to protect against atherosclerosis.

When there is damage to the endothelium, the formation of an atherosclerotic plaque forms and causes THICKENING of the intimal layer which causes it to protude into the lumen of the vessel and narrow it.

Front 3

Describe the structure of an atherosclerotic plaque.

Back 3

The lipid core is surrounded by a fibrous cap.

Front 4

What can be found within the lipid core of an atherosclerotic plaque?

Back 4

-Smooth m. cells (allows growth & proliferation of the plaque)
-foamy macrophages filled with lipid)
-T-lymphocytes (inflammation)

Front 5

The progression of atherosclerotic plaques starts around decade of life? What triggers the formation of atherosclerotic plaques?

Back 5

2nd & progresses depending on genetics and lifestyle
-damage to the endothelium triggers the formation of a plaque

Front 6

What are the normal functions of endothelium?

Back 6

Permeability barrier (enhances or retards the movement of macromolecules in & out of the vascular system)
-transduces various signals
-produces various signals

Front 7

What is probably the role of the endothelium in the beginning stages of atherosclerosis?

Back 7

Increased permeability to lipoproteins

Front 8

Explain the role of factors released by the endothelium.

Back 8

Factors are released to modulate the state of the vessel (i.e to make it thrombotic vs. anti-thrombotic or anti or pro-inflammatory)

Front 9

The release of factors from the endothelium favor what conditions in normal endothelium? What influences a shift from these conditions?

Back 9

-inhibition of thrombosis, growth, and inflammation
-a shift from these conditions occurs when there is a problem in the vessel wall (and conditions will revert back once the problem is solved).

Front 10

The release of factors maintain the shift of?

Back 10

-the shift of the vasculature during its healthy state and damaged or problematic state (i.e. inflammatory, thrombic)

Front 11

What is the role of NO on the vasculature? Where is it released?

Back 11

-NO causes vasorelaxation and is a FACTOR released by the vascular endothelium

Front 12

What factors induce the release of NO from the endothelial cells?

Back 12

-Ach
-Bradykinin
-adenosine
-shear stress on the vasculature

Front 13

How does the presence of Ach affect the endothelium when there is atherosclerosis in the wall of the vessel?

Back 13

Normally Ach induces the release of NO from vascular endothelium, but when there is atherosclerosis present, the endothelial cells DO NOT release NO & instead constrict

Front 14

When a person has NO frank atherosclerosis, just risk factors, how does the endothelium respond in the presence of ACh? Does this change as the risk facors a person has increases?

Back 14

There is a reduced ability to release NO in a person with no frank atherosclerosis, just risk factors. As a person has increasing #'s of risk factors, there is a further decrease in NO release from the endothelium.

Front 15

Where is NO made? How is NO made? What cofactors are neccessary?

Back 15

-NO is made in the endothelial cells.
-L-arginine is converted to NO via NO synthase (eNOS) and has several cofactors:calmodulin, NADPH, BH4.

-After being produced in the endothelial cell, it moves in the media of the vessel to act on smooth muscle cells

Front 16

NO is made here, but completes its function here?

Back 16

Made in endothelium, completes its action in the media's smooth mucle layer

Front 17

Once, in the smooth muscle cell, how does NO work? What is the result of this action?

Back 17

NO stimulates Guanyl cyclase to convert GTP to produce cGMP, which causes smooth muscle relaxation & dilation of the artery

Front 18

How is the release of NO regulated?

Back 18

Regulated both chronically and acutely:
Acute: increase in L-arginine or an increase in factors that stimulate the release of NO (Ach and bradykinin) OR by changing the shear stress that acts on endothelial cells.

Chronically: by the stimulation of growth factors or chronic changes in shear stress on the endothelial cell

Front 19

What occurs when sheer stress is placed on the endothelial cell?

Back 19

-Shear stress stimulates the release of NO

Front 20

How is NO broken down?

Back 20

By heme containing compounds (i.e. RBC is important for NO disposal)
OR by NO combining with superoxide anions.

Front 21

What is the role of NO on the following cells:
neighboring endothelium
platelets
monocytes
smooth muscle

Back 21

-Can act on neighboring endothelial cells & inhibit the production of leukocyte adhesion molecules
-mono
-inhibits aggregation of and adhesion of platelets (anti-thrombotic)
-smooth muscle cells: vasorelaxation and inhibits migration & proliferation of these cells

THESE ARE ALL ANTI-ATHEROGENIC MECHANISMS (prevents plaque formation)

Front 22

When endothelium is healthy, NO is considered an __________ molecule.

Back 22

-Anti-atherogenic

Front 23

Explain how the presence of risk factors can lead to the generation of atherosclerosis.

Back 23

-the presence of hyperlipidemia, DM, hypertension, and smoking cause the release of factors that favor vasoconstriction, thrombosis, inflammation, growth and proliferation, and increase lipid deposition on the wall of the vessel.

Front 24

Explain how oxidative stress can lead to atherogenesis.

Back 24

-normally oxidative molecules are buffered with antioxidants to maintain redox homeostasis
-in the presence of risk factors, the # of oxidants increase and it leads to oxidative stress on the endothelial cells
-oxidative stress leads to the up-regulation of genes that for factors that are PRO-athergenic

Front 25

Explain the role of superoxide and NO.

Back 25

Superoxide is an oxidant that inactivates NO, and when it combines with NO it leads to the production of peryoxynitrate, another strong oxidant

Front 26

When oxidative stress is occurring, what happens to NO?

Back 26

When there is oxidative stress, the accumulation of oxidative molecules causes a decrease in NO and the production of stronger oxidative molecules.

Front 27

Why is NO decreased during oxidative stress?

Back 27

Because it combines with the oxidative molecules and forms other oxidants (peryoxinitrate)

Front 28

ACE enzyme is found 2 places in the body.

Back 28

The tissues (heart, vessels, kidneys) & circulating in plasma

Front 29

Oxidant stress causes the release of ____________ from vessels?

Back 29

ACE enzyme found on the tissue (& blood vessels) produces Ang-2

Front 30

When there is oxidative stress, there is increased release of _______? What is the effect of this?

Back 30

Ang-2; increased Ang-2 stimulates ang-2 type 1 receptors and results in the production of super oxide anions

**Remember, the production of superoxide causes it to combine with NO and decrease levels of NO.

Front 31

ACE has 2 functions in the vessel, what are they.

Back 31

-production of Ang-2 and the degradation of bradykinin (which is a stimulator of the release of NO.

Front 32

Ang-2 is responsible for the production of this molecule? What is the role of this molecule in atherosclerosis development?

Back 32

Growth factor (also secreted by activated macrophages + is overexpressed in atherosclerosis); which is a smooth muscle cell chemoattractant

Front 33

Smooth muscle cells are apart of the ____________ component of an atherosclerotic plaque.

Back 33

lipid core

Front 34

Describe the change that occurs in smooth muscle cells in the resting state vs. the atherosclerotic state. What affect does smooth muscle cells have on the plaque?

Back 34

Smooth muscle cells are in a resting state in healthy tissue & when acted upon by growth factors, they become activated and produce collagen & proteoglycan which are important for growth of the plaque.

Front 35

A atherosclerotic plaque can grow by what mechanism?

Back 35

The recruitment of smooth muscle cells via growth factors and their production of collagen and proteoglycan (causes growth).

Front 36

What is the proposed mechanism for the first steps in atherogenesis?

Back 36

Person has a diet high in cholesterol --> and there is an accumulation of of LDL-lipoprotein particles in the intima & they bind to proteoglycans found in the intima.
-the proteoglycans hold the lipoproteins in the intima
-the lipoproteins become oxidized and oxidized LDL is readily taken up by intimal macrophages.

Front 37

_________ induces the expression of leukocyte adhesion molecules.

Back 37

Oxidative stress (including oxidized lipoproteins)

Front 38

What is the role of I-CAM & V-CAM in the endothelium?

Back 38

Oxidative lipoproteins in the intima cause the production of of I-CAM and V-CAM and they attract monocytes & T-lymphocytes to attache to the endothelial surface.

Front 39

This is the earliest sign of an atherosclerotic lesion.

Back 39

Foam cells (lipid laden macrophages).

Front 40

MCP-1's and M-CSF's function?

Back 40

MCP-Macrophage chemoattractant
CSF- induces the expression of scavenger receptors to take up oxidized lipoproteins

Front 41

Plaques are more likely to be found in what part of the artery. What does this imply?

Back 41

The proximal portion of branch points of vessels
-plaques are more likely to be found at areas of lower flow states (low shear stress)

Front 42

Describe the distribution of atherosclerotic plaques in blood vessels. Why is it this way?

Back 42

It is uneven distribution due to the areas of low shear stress.

Front 43

Increased laminar shear stress induces ___________?

Back 43

The release of NO

Front 44

How does risk factor modification decrease the risk for atherosclerosis?

Back 44

Lowering risk factors can decrease the endothelial damage, which is responsible for the initiation of atherosclerosis.