Chapter 10: Blood vessels

Question 1

Fill in: Vascular injury leading to EC loss or dysfunction *decreases/stimulates* SMC growth, ECM *breakdown/synthesis*, and *thickening/thinning* of the vascular wall

Answer 1

Stimulates, synthesis and thickening respectively

Question 2

Explain from inside out the different layers of vessels

Answer 2

Tunica intima - internal elastic lamina - media - adventitia

Question 3

Where, in the different layers of the vessels, can SMCs be found? (when there’s no injury)

Answer 3

Media

Question 4

Where, in the different layers of the vessels, can elaboration of ECM be found? (in case of endothelial injury)

Answer 4

Intima

Question 5

SMCs can migrate from the media to the intima in case of injury. How can neointimal SMCs be identified from medial SMCs?

Answer 5

Neointimal SMCs are not contractile like medial SMCs, but do have the capacity to divide and have a considerably greater synthetic capacity

Question 6

Can the intimal thickening (migration of SMCs) also be found outside of injury?

Answer 6

Yes, this also occurs as a part of ‘normal aging’

Question 7

What does arteriosclerosis literally mean?

Answer 7

Hardening of the arteries

Question 8

What does arteriosclerosis reflect?

Answer 8

Arterial wall thickening and loss of elasticity

Question 9

What is atherosclerosis?

Answer 9

Atherosclerosis is characterized by intimal lesions called atheromas (or atheromatous or atherosclerotic plaques) that impinge on the vascular lumen and can rupture to cause sudden occlusion

Question 10

There are four distinct types of arteriosclerosis. What are they?

Answer 10

• arteriolosclerosis - Mönckerberg medial sclerosis - Fibromuscular intimal hyperplasia - atherosclerosis

Question 11

What is arteriolosclerosis

Answer 11

Arteriolosclerosis affects small arteries and arterioles and may cause downstream ischemic injury

Question 12

What is Mönckerberg medial sclerosis?

Answer 12

Mönckeberg medial sclerosis is characterized by the presence of calcific deposits in muscular arteries, usually centered on the internal elastic lamina, and typically in individuals older than 50 years of age. The lesions do not encroach on the vessel lumen and usually are not clinically significant.

Question 13

What is fibromuscular intimal hyperplasia?

Answer 13

Fibromuscular intimal hyperplasia is a non-atherosclerotic process that occurs in muscular arteries larger than arterioles. This is predominantly an SMC- and ECM-rich lesion driven by inflammation or by mechanical injury

Question 14

What are atherosclerotic plaques?

Answer 14

They are raised leasions composed of soft friable (grumous) lipid cores (mainly cholesterol (esters), with necrotic debris) covered by fibrous caps

Question 15

What are complications of (enlarged) atherosclerotic plaques?

Answer 15

They may mechanically obstruct vascular lamina, leading to stenosis. They are also prone to rupture, that may result in thrombosis and sudden occlusion of the vessel

Question 16

The thickness of the intimal lesions also may be sufficient to impede the perfusion of the underlying media, which may be weakened by …. caused by subsequent inflammation

Answer 16

ischemia and by changes in the ECM

Question 17

When looking at the basis structure of an atheromatous plaque, the layers are: a fibrous cap, necrotic center and media. What’s inside the fibrous cap?

Answer 17

smooth muscle cells, macrophages, foam cells, lymphocytes, collagen, elastin, proteoglycans, neovascularization

Question 18

When looking at the basis structure of an atheromatous plaque, the layers are: a fibrous cap, necrotic center and media. What’s inside the necrotic center?

Answer 18

cell debris, cholesterol crystals, foam cells, calcium

Question 19

When looking at the basis structure of an atheromatous plaque, the layers are: a fibrous cap, necrotic center and media. What’s inside the media?

Answer 19

SMCs

Question 20

What are the major risk factors for atherosclerosis?

Answer 20

Nonmodifiable (constitutional): - genetic abnormalities - family history - increasing age - male gender Modifable: - hyperlipidemia - hypertension - cigarette smoking - DM - inflammation

Question 21

p371-372 (until pathogenesis) is not taken up in these flashcards. They were not discussed in the lecture and i personally think it’s not that relevant

Answer 21

Feel free to read it yourself tho :) (and epidemiology on p370 is also not in here btw)

Question 22

What does the response-to-injury hypothesis mean?

Answer 22

This model views atherosclerosis as a chronic inflammatory response of the arterial wall to endothelial injury

Question 23

What does lesion progression involve?

Answer 23

Interaction of modified lipoproteins, monocyte-derived macrophages, T lymphocytes, and the cellular constituents of the arterial wall

Question 24

According to the response-to-injury hypothesis/model, there are five steps involved. What are these?

Answer 24

1. Normal EC.

2,. Endothelial injury with monocyte and platelet adhesion.

3. Monocyte and smooth muscle cell migration into the intima, with macrophage activation.
4. Macrophage and smooth muscle cell uptake of modified lipids and further activation.
5. Intimal smooth muscle cell proliferation and extracellular matrix elaboration, forming a well-developed plaque.

Question 25

According to the response-to-injury hypothesis/model, there are a couple of pathogenic events that result in atherosclerosis. What are they? (they will be discussed in detail shortly)

Answer 25

• EC injury—and resultant endothelial dysfunction— leading to increased permeability, leukocyte adhesion, and thrombosis
• Accumulation of lipoproteins (mainly oxidized LDL and cholesterol crystals) in the vessel wall
• Platelet adhesion
• Monocyte adhesion to the endothelium, migration into the intima, and differentiation into macrophages and foam cells
• Lipid accumulation within macrophages, which respond by releasing inflammatory cytokines
• SMC recruitment due to factors released from activated platelets, macrophages, and vascular wall cells
• SMC proliferation and ECM production

Question 26

(globally) explain the what injury of ECs can be induced by

Answer 26

Mechanical denudation, hemodynamic forces, immune complex deposition, irradiation, or chemicals

Question 27

Fill in: EC injury results in intimal *thickening/thinning*

Answer 27

thickening

Question 28

Where do early human atherosclerotic lesions begin?

Answer 28

At the sites of intact, but dysfunctional, endothelium

Question 29

How does a dysfunctional EC contribute to the development of atherosclerosis?

Answer 29

Increased permeability, enhanced leukocyte adhesion, and/or altered gene expression

Question 30

What are suspected triggers of early atheromatous lesions / endothelial dysfunction?

Answer 30

Hypertension, hyperlipidemia, toxins from cigarette smoke, and homocysteinemia. Inflammatory cytokines (e.g., tumor necrosis factor [TNF]) also can stimulate proatherogenic patterns of EC gene expression. Nevertheless, the two most important causes of endothelial dysfunction are hemodynamic disturbances and hypercholesterolemia.

Question 31

How is the importance of hemodynamic factors in atherogenesis illustrated in studies?

Answer 31

Plaques tend to occur at ostia of exiting vessels, at branch points and along the posterior wall of the abdominal aorta, where there is turbulent blood flow

Question 32

In vitro studies further demonstrate that nonturbulent laminar flow leads to the induction of … whose products protect against atherosclerosis Follow up question: what do these inducted ‘substances’ explain?

Answer 32

• endothelial genes
• They explain the nonrandom localization of early atherosclerotic lesions.

Question 33

Lipids typically are transported in the bloodstream bound to specific

Answer 33

Apoproteins (forming lipoprotein complexes)

Question 34

What is dyslipoproteinemia?

Answer 34

Dyslipoproteinemia, also referred to as dyslipidemia, encompasses a range of disorders of lipoprotein lipid metabolism that include both abnormally high and low lipoprotein concentrations, as well as abnormalities in the composition of these lipoprotein particles.

Question 35

What are some causes of dyslipoproteinemias? (don’t learn by heart)

Answer 35

Mutations in genes that encode apoproteins or lipoprotein receptors, or from disorders that derange lipid metabolism, e.g., nephrotic syndrome, alcoholism, hypothyroidism, or diabetes mellitus.

Question 36

Fill in: Common lipoprotein abnormalities in the general population include (1) *decreased/increased* LDL cholesterol levels, (2) *decreased/increased* HDL cholesterol levels, and 3) *decreased/increased* levels of lipoprotein(a).

Answer 36

increased, decreased and increased respectively

Question 37

What are several lines in evidence that implicate hypercholesterolemia in atherogenesis? (in included these for the sake of completeness, just skim and skip :))

Answer 37

• The dominant lipids in atheromatous plaques are cholesterol and cholesterol esters. • Genetic defects in lipoprotein uptake and metabolism that cause hyperlipoproteinemia are associated with accelerated atherosclerosis. Thus, homozygous familial hypercholesterolemia, caused by defective LDL receptors and inadequate hepatic LDL uptake, can lead to myocardial infarction by 20 years of age. • Other genetic or acquired disorders (e.g., diabetes mellitus, hypothyroidism) that cause hypercholesterolemia lead to premature atherosclerosis. • Epidemiologic analyses (e.g., the Framingham study) demonstrate a significant correlation between the levels of total plasma cholesterol or LDL and the severity of atherosclerosis. • Lowering serum cholesterol by diet or drugs slows the rate of progression of atherosclerosis, causes regression of some plaques, and reduces the risk for cardiovascular events.

Question 38

What happens in chronic hyperlipidemia, particularly hypercholesterolemia, that cause impairment of EC function?

Answer 38

Increasing local oxygen free radical production; among other things, oxygen free radicals accelerate NO decay, damping its vasodilator activity.

Question 39

Lipoproteins accumulate within the intima, where they are hypothesized to generate two pathogenic derivatives:

Answer 39

Oxidized LDL and cholesterol crystals

Question 40

Normal vessels do not bind inflammatory cells. Early in atherogenesis, however, dysfunctional ECs express adhesion molecules that promote leukocyte adhesion, in particular, … and … which migrate into the intima under the influence of locally produced chemokines.

Answer 40

monocytes and T cells

Question 41

Once the monocyte is migrated into the intima, what happens then?

Answer 41

Monocytes differentiate into macrophages and avidly engulf lipoproteins, including oxidized LDL and small cholesterol crystals. (Activated macrophages also produce toxic oxygen species that drive LDL oxidation and elaborate growth factors that stimulate SMC proliferation)

Question 42

Once the T lymphocytes are recruited to the intima, they …

Answer 42

Interact with the macrophages and also contribute to chronic inflammation. Activated T cells in the growing intimal lesions elaborate inflammatory cytokines (e.g., IFN-γ), which stimulate macrophages, ECs, and SMCs. (it is unclear how they are activated!!)

Question 43

As a consequence of the chronic inflammatory state, activated leukocytes and vascular wall cells release growth factors that promote ….

Answer 43

SMC proliferation and ECM synthesis

Question 44

What does intimal SMC proliferation and ECM deposition lead to?

Answer 44

conversion of the earliest lesion, a fatty streak, into a mature atheroma, thus contributing to the progressive growth of atherosclerotic lesions

Question 45

Several growth factors are implicated in SMC proliferation and matrix synthesis. Such as which?

Answer 45

platelet-derived growth factor (released by locally adherent platelets, macrophages, ECs, and SMCs), fibroblast growth factor, and TGF-α

Question 46

The recruited SMCs synthesize ECM. What substance is mostly synthesized and what does it do?

Answer 46

Collagen, stabilizes atherosclerotic plaques

Question 47

However, activated inflammatory cells in atheromas also can cause intimal SMC apoptosis and breakdown of matrix, leading to the development of …

Answer 47

unstable plaques

Question 48

Please look at the next figure, this summarizes/visualizes all that we have discussed thus far

Answer 48

Yes ma’am

Question 49

The development of atherosclerosis tends to follow a series of mophologic changes, starting with fatty streaks. What do these fatty streaks look like and what do they contain?

Answer 49

Fatty streaks begin as minute yellow, flat macules that coalesce into elongated lesions, 1 cm or more in length. They are composed of lipid-filled foamy macrophages but are only minimally raised and do not cause any significant flow disturbance.

Question 50

True/false: Fatty streaks can appear in the aortas of infants.

Answer 50

True! Of the ages of younger than 1. They are virtually present in all children of 10y.o

Question 51

The development of atherosclerosis tends to follow a series of mophologic changes. After fatty streaks, atherosclerotic lesions may appear. How do they look?

Answer 51

The key features of these lesions are intimal thickening and lipid accumulation. Atheromatous lesions are white to yellow raised lesions; they range from 0.3 to 1.5 cm in diameter but can coalesce to form larger masses.

Question 52

Atherosclerotic plaques have three principal components:

Answer 52

(1) cells, including SMCs, macrophages, and T cells; (2) ECM, including collagen, elastic fibers, and proteoglycans; and (3) intracellular and extracellular lipid (see Fig. 10.13A and B).

Question 53

Plaques generally progressively enlarge over time through cell death and degeneration, synthesis and degradation of ECM (remodeling), and thrombus organization. Atheromas also often undergo …

Answer 53

Calcification!!!

Question 54

Atherosclerotic plaques are susceptible to several clinically important changes. Such as which? (4 answers)

Answer 54

• Rupture, ulceration, or erosion. • Hemorrhage into a plaque. • Atheroembolism. • Aneurysm formation.

Question 55

What are the consequences of rupture, ulceration or erosion of the luminal surface of atheromatous plaques?

Answer 55

The plaque exposes highly thrombogenic substances and induces thrombus formation. Thrombi may partially or completely occlude the lumen, leading to tissue ischemia

Question 56

What are the consequences of hemmorrhage into a plaque?

Answer 56

Rupture of the overlying fibrous cap or of the thin-walled vessels in the areas of neovascularization can cause intra-plaque hemorrhage; the resulting hematoma may cause rapid plaque expansion or plaque rupture.

Question 57

What are the consequences of atheroembolism?

Answer 57

Ruptured plaque can discharge debris into the blood, producing microemboli composed of plaque contents.

Question 58

How can aneurysm formation occur?

Answer 58

Atherosclerosis-induced pressure or ischemic atrophy of the underlying media, with loss of elastic tissue, causes structural weakening that can lead to aneurysmal dilation and rupture.

Question 59

Which vessels are most commonly involved in atherosclerosis?

Answer 59

Large elastic arteries (e.g., aorta, carotid, and iliac arter- ies) and large- and medium-sized muscular arteries (e.g., coronary, renal, and popliteal arteries)

Question 60

What are the major clinical consequences of atherosclersosis?

Answer 60

Myocardial infarction (heart attack), cerebral infarction (stroke), aortic aneurysm, and peripheral vascular disease (gangrene of extremities)

Question 61

Please take a good look at the next slide, it will help you see the overall picture

Answer 61

Robbins Basic Pathology by Vinay Kumar, Abul K. Abbas, Jon C. Aster

Question 62

At early stages, remodeling of the media tends to preserve the luminal diameter by increasing the overall vessel circumference. Owing to limits on remodeling, however, eventually the expanding atheroma may impinge on blood flow. Although this most commonly happens as a consequence of acute plaque change (described next), it can also occur gradually, with … being the tipping point at which chronic occlusion limits flow so severely that tissue demand exceeds supply

Answer 62

critical stenosis

Question 63

Plaque erosion or rupture typically triggers thrombosis, leading to partial or complete vascular obstruction and often tissue infarction. Which three general categories do plaque changes fall into?

Answer 63

• Rupture/fissuring, exposing highly thrombogenic plaque constituents • Erosion/ulceration, exposing the thrombogenic subendothelial basement membrane to blood • Hemorrhage into the atheroma, expanding its volume

Question 64

Fill in: Plaques responsible for myocardial infarctions and other acute coronary syndromes often are *asymptomatic/symptomatic* before the acute event

Answer 64

asymptomatic

Question 65

Certain types of plaques are believed to be at particularly high risk of rupturing. Which are these?

Answer 65

Plaques that contain large numbers of foam cells and abundant extracellular lipid, plaques that have thin fibrous caps containing few SMCs, and plaques that contain clusters of inflammatory cells.

Question 66

How are plaques at high risk for rupture referred to as?

Answer 66

Vulnerable/unstable plaques

Question 67

Fill in: In general, plaque inflammation *decreases/increases* collagen degradation and *decreases/increases* collagen synthesis, thereby *stabilizing/destabilizing* the mechanical integrity of the cap

Answer 67

increases, decreases, destabilizing, respectively

Question 68

What is the difference between vulnerable and stable atherosclerotic plaques?

Answer 68

Stable plaques have densely collagenized and thickened fibrous caps with minimal inflammation and negligible underlying atheromatous cores, whereas vulnerable plaques have thin fibrous caps, large lipid cores, and increased inflammation.

Question 69

Have a close look at the next figure

Answer 69

From robbins basic pathology

Question 70

Of interest, statins may have a beneficial effect by … (2 answers)

Answer 70

Reducing circulating cholesterol levels and stabilizing plaques through a reduction in plaque inflammation

Question 71

What happens because of adrenergic stimulation (e.g. intense emotions)

Answer 71

They increase systemic blood pressure or induce local vasoconstriction, thereby increasing the mechanical stress on a given plaque

Question 72

Do all plaque ruptures result in occlusive thromboses with catastrophic consequences?

Answer 72

No