Chapter 11 – Blood Vessels: Vascular Wall Cells & Their Response to Injury

Question 1

What are the main cellular components of the blood vessels play central roles in vascular biology and pathology?

Answer 1

endothelial cells and smooth muscle cells

Question 2

What is critical for maintaining vessel wall homeostasis and circulatory function?

Answer 2

Endothelium

Question 3

What are Weibel-Palade bodies?

Answer 3

• Endothelial cells contain in the Endothelial cells ,
• intracellular membrane-bound storage organelles for von Willebrand’s factor ( Chapter 4 ).

Question 4

What can be used to identify endothelial junctions?

Answer 4

Antibodies to von Willebrand’s factor and/or
platelet-endothelial cell adhesion molecule-1 (PECAM-1 or CD31, a protein localized to
interendothelial junctions) can be used to identify endothelial cells immunohistochemically

Question 5

Vascular endothelium is a multifunctional tissue with a wealth of synthetic and metabolic
properties; at baseline it has several constitutiveactivities critical for normal vessel homeostasis

T or F

Answer 5

True

Question 6

What are the important funcitons of endothelial cells?

Answer 6

• maintain a nonthrombogenic blood-tissue interface (until clotting is necessitated by local injury, Chapter 4 ),
• modulate vascular resistance,
• metabolize hormones,
• regulate inflammation, and
• affect the growth of other cell types, particularly smooth muscle cells.

In most regions the interendothelial junctions are substantially impermeable. However, tight endothelial cell junctions can loosen under the influence of hemodynamic factors (e.g., high blood pressure) and/or vasoactive agents (e.g., histamine in inflammation), resulting in the flooding of adjacent tissues by electrolytes and protein; in inflammatory states, even leukocytes can slip between adjacent endothelial cells

Question 7

TABLE 11-1 – Endothelial Cell Properties and Functions

MAINTENANCE OF PERMEABILITY BARRIER

Answer 7

• MAINTENANCE OF PERMEABILITY BARRIER
  
  • ELABORATION OF ANTICOAGULANT, ANTITHROMBOTIC, FIBRINOLYTIC REGULATORS
  • ELABORATION OF PROTHROMBOTIC MOLECULES
• EXTRACELLULAR MATRIX PRODUCTION (COLLAGEN, PROTEOGLYCANS)
  
  • MODULATION OF BLOOD FLOW AND VASCULAR REACTIVITY
  • REGULATION OF INFLAMMATION AND IMMUNITY
  • REGULATION OF CELL GROWTH
  • OXIDATION OF LDL

Question 8

TABLE 11-1 – Endothelial Cell Properties and Functions

MAINTENANCE OF PERMEABILITY BARRIER

ELABORATION OF ANTICOAGULANT, ANTITHROMBOTIC, FIBRINOLYTIC REGULATORS

Answer 8

• Prostacyclin
• Thrombomodulin
• Heparin-like
• molecules
• Plasminogen activator

Question 9

TABLE 11-1 – Endothelial Cell Properties and Functions

MAINTENANCE OF PERMEABILITY BARRIER

ELABORATION OF PROTHROMBOTIC MOLECULES

Answer 9

• Von Willebrand’s factor
• Tissue factor
• Plasminogen activator inhibitor

Question 10

TABLE 11-1 – Endothelial Cell Properties and Functions

MAINTENANCE OF PERMEABILITY BARRIER

ELABORATION OF PROTHROMBOTIC MOLECULES

Answer 10

• Von Willebrand’s factor
• Tissue factor
• Plasminogen activator inhibitor

Question 11

TABLE 11-1 – Endothelial Cell Properties and Functions

EXTRACELLULAR MATRIX PRODUCTION (COLLAGEN, PROTEOGLYCANS)

MODULATION OF BLOOD FLOW AND VASCULAR REACTIVITY

Answer 11

• Vasconstrictors: endothelin,
• ACE
• Vasodilators: NO, prostacyclin

Question 12

TABLE 11-1 – Endothelial Cell Properties and Functions

EXTRACELLULAR MATRIX PRODUCTION (COLLAGEN, PROTEOGLYCANS)

REGULATION OF INFLAMMATION AND IMMUNITY

Answer 12

• IL-1, IL-6, chemokines
• Adhesion molecules: VCAM-1, ICAM, E-selectin, Pselectin
• Histocompatibility antigens

Question 13

TABLE 11-1 – Endothelial Cell Properties and Functions

EXTRACELLULAR MATRIX PRODUCTION (COLLAGEN, PROTEOGLYCANS)

REGULATION OF CELL GROWTH

Answer 13

• Growth stimulators: PDGF, CSF,
• FGF
• Growth inhibitors: heparin, TGF-β

Question 14

Although endothelial cells share many general attributes, endothelial cell populations that line
different portionsof the vascular tree (large vessels vs. capillaries, arterial vs. venous) have
distinct transcriptional repertoires and behavior. [9]

T or F

Answer 14

True

There is also substantial phenotypic
variability depending on specific anatomic site. Thus, endothelial cells in liver sinusoids or in
renal glomeruli are fenestrated (they have holes, presumably to facilitate filtration), while the
endothelial cells of the central nervous system (with the associated perivascular cells) create an
impermeable blood-brain barrier.

Question 15

What is endothelial activatation?

Answer 15

Structurally intact endothelial cells can respond to various pathophysiologic stimuli by adjusting
their usual (constitutive) functions and by expressing newly acquired (inducible) properties—a
process termed endothelial activation ( Fig. 11-2 ). [10,] [11]

Question 16

What are the Inducers of endothelial activation?

Answer 16

• cytokines and bacterial products, which cause inflammation and septic shock ( Chapter2
• hemodynamic stresses and lipid products, critical to the pathogenesis of atherosclerosis (see later);
• advanced glycosylation end products (important in diabetes, Chapter 24 );
• as well as viruses, complement components, and hypoxia.

Question 17

Answer 17

FIGURE 11-2 Endothelial cell responses to environmental stimuli. Certain cues (e.g.,
laminar flow and constant growth factor levels) lead to stable endothelial cell activation that
maintains a nonthrombotic interface with appropriate smooth muscle cell tone. Pathologic
mediators or excessive stimulation by normal physiologic pathways (e.g., increased
inflammatory cytokines) can result in endothelial cell dysfunction. VEGF, vascular endothelial
growth factor

Question 18

What is endothelial dysfunction?

Answer 18

Endothelial dysfunction is defined as an altered phenotype that impairs vasoreactivity or
induces a surface that is thrombogenic or abnormally adhesive to inflammatory cells.

It is

• *responsible, at least in part, for the initiation of thrombus formation, atherosclerosis,** and the
• *vascular lesions of hypertensio**n and other disorders.

Certain forms of endothelial cell
dysfunction are rapid in onset (within minutes), reversible, and independent of new protein
synthesis (e.g., endothelial cell contraction induced by histamine and other vasoactive
mediators that cause gaps in venular endothelium, Chapter 2 ).

Other changes involve
alterations in gene expression and protein synthesis and may require hours or even days to
develop.

Question 19

What is the function of Vascular Smooth Muscle Cells?

Answer 19

As the predominant cellular element of the vascular media, smooth muscle cells play important
roles in normal vascular repair and pathologic processes such as atherosclerosis

• Smooth muscle cells have the capacity to proliferate when appropriately stimulated; they can also synthesize ECM collagen, elastin, and proteoglycans and elaborate growth factors and cytokines.
• Smooth muscle cells are also responsible for the vasoconstriction or dilation that occurs in response to physiologic or pharmacologic stimuli.

Question 20

The migratory and proliferative activities of smooth muscle cells are regulated by growth
promoters and inhibitors.

What are the promoters?

Answer 20

• PDGF,
• as well as endothelin-1, thrombin,
• fibroblast growth factor (FGF),
• interferon-γ (IFN-γ), and
• interleukin-1(IL-1).

Question 21

What are your inhibitors that regulate migratory and proliferative activities of smooth muscle cells are regulated

Answer 21

• heparan sulfates,
• nitric oxide, and
• TGF-β. ]

Question 22

What are your other regulators for Vascular Smooth Muscle Cells?

Answer 22

Other regulators include the renin-angiotensin system (e.g., angiotensin II), catecholamines, the estrogen receptor, and osteopontin, a component of the
ECM. [13]

Question 23

What is the Stereotypic Response To Vascular Injury.?

Answer 23

Intimal Thickening

Question 24

What stimulates smooth muscle
cell growth and associated matrix synthesis that thickens the intima?

Answer 24

Vascular injury—with endothelial cell loss or even just dysfunction—

Question 25

Healing of injured vessels is analogous to what ?

Answer 25

Healing of injured vessels is analogous to the **healing process that occurs in other damaged tissue**s ( Chapter 3 ); in vessels, **it results in the formation of a neointima**

Question 26

What happens to the endothelial cells during the healing process?

Answer 26

During the healing process, **endothelial cells** that **fill areas of denudation may migrate from adjacent uninjured areas or may be derived from circulating precursors.**[14]

Question 27

What happens to the medial smooth muscle cell during the process of healing?

Answer 27

Medial smooth muscle cells or smooth muscle precursor cells also migrate into the intima, proliferate, and synthesize ECM in much the same way that fibroblasts fill in a wound ( Fig. 11-3 ). The **resulting neointima** is **typically completely covered by endothelial cells**. This **neointimal response occurs with any form of vascular damage** or **dysfunction,** regardless of cause. Thus, intimal thickening is the stereotypical response of the vessel wall to any insult.

Question 28

Answer 28

FIGURE 11-3 Schematic of intimal thickening, emphasizing smooth muscle cell migration and proliferation within the intima, with associated ECM synthesis. Intimal smooth muscle cells may derive from the underlying media or may be recruited from circulating precursors; they are shown in a different color from the medial cells to emphasize that they have a proliferative, synthetic, and noncontractile phenotype distinct from medial smooth muscle cells.

Question 29

What is the distinction of neointimal smooth muscle phenotype from that of medial smooth muscle cell?

Answer 29

neointimal smooth muscle cells **do not contract like medial smooth muscle cells** but h**ave the capacity to divide.** Although these neointimal cells have long been thought to be derived from de-differentiation of smooth muscle cells migrating from the underlying media, there is increasing evidence that the **intimal smooth muscle cells are at least in part derived from circulating precursor cells**

Question 30

The migratory, proliferative, and synthetic activities of the intimal smooth muscle cells are physiologically regulated by what?

Answer 30

* products derived from platelets * , endothelial cells, and macrophages, as well as by activated coagulation and complement factors. Promoters: stimulate neointimal smooth muscle cells, * PDGF, endothelin-1, thrombin, FGF, IFN-γ, and IL-1 Inhibitors: antagonize their growth. * heparan sulfates, * nitric oxide, and TGF-β

Question 31

With time and restoration and/or normalization of the endothelial layer, what happens to the intimal smooth muscle cells?

Answer 31

With time and restoration and/or normalization of the endothelial layer, the intimal smooth muscle cells **can return to a nonproliferative state.** However, the healing response results in permanent intimal thickening.

Question 32

What is the result of the healing response of the blood vessel?

Answer 32

**permanent intimal thickening.** With persistent or recurrent insults, excessive thickening can cause narrowing or stenosis of small and medium-sized blood vessels (e.g., atherosclerosis, see below), impeding downstream tissue perfusion.

Question 33

In what situation does intimal thickening normally occurs?

Answer 33

intimal thickening **also occurs in otherwise normal** arteries as a **result of maturation and aging**. In adult coronaries, for example, the **intima and the media are frequently of approximately equal thickness.** Such **age-related intimal change is typically of no consequence**, in part **because a compensatory outward remodeling of the vessel results in little net change in the luminal diameter** [18] ; it also suggests **that not all intimal thickening is a harbinger of** disease.