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Case 4 > The importance of endothelial function on health and disease > Flashcards

The importance of endothelial function on health and disease Flashcards

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1
Q

What is the vascular system composed of

A

Arteries -> arterioles -> capillaries -> venules -> veins

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2
Q

What are the different types of arterioles

A

Conduit (elastic)- recoil. Muscular (distributing)- dilate. Terminal (end) arteries

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3
Q

What is the typical blood vessel structure

A

Endothelium, tunica initma, internal elastic lamina, tunica media, external elastic lamina, tunica adventitia.

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4
Q

What is the tunica media composed of

A

Smooth muscle cells

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5
Q

What is the tunica adventitia’s function

A

It provides structure

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6
Q

What does the tunica intima contain

A

The endothelium and basement mebrane

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7
Q

What do capillaries consist of

A

Single cells

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8
Q

Which direction is the endothelium elongated in

A

The direction of flow

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9
Q

Is the endothelium flat

A

No, it protrudes into the lumen of the cell

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10
Q

Where is Von Willebrand factor produced

A

In endothelial cells

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11
Q

What is PGI2

A

Prostacyclin, it is antithrombotics and acts by inhibiting aggregation of platelets

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12
Q

Where is PGI2 released from

A

Endothelial cells

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13
Q

What do endothelial cells have an obligatory role in in relation to arterial smooth muscle

A

Obligatory role in relaxation of arterial smooth muscle by acetlycholine

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14
Q

What happens when acetylcholine is introduced to an artery with its endothelium intact

A

Relaxation is induced

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15
Q

What affect does histamine have on coronary arteries

A

The greater the concentration of histamine the more the muscle contracts resulting in an increase in perfusion pressure

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16
Q

Why do vessels have a basal level of tone

A

To respond to stimuli. To vasodilate allowing increased localised blood flow and tissue perfusion (such as that required by increased metabolic demand- high tone in skeletal muscle creates a “reserve”, potential for increased capacity

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17
Q

What presents a blood vessel constricting too much

A

Basal release of EDRF

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18
Q

What is the stimulus for basal release

A

Flow- the endothelial cell surface senses haemodynamic mechanical forces, such as shear stress, with transduction into intracellular signalling events leading to release of EDRF

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19
Q

What is EDRF

A

Endothelial dervied relaxing factor

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20
Q

What does EDRF ensure

A

There is always tone in the vessel wall= vessel can respond to stimuli

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21
Q

What was EDRF shown to be

A

Nitric oxide (NO)

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22
Q

Describe stimulation of NO prodction

A

Agonist stimulated

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23
Q

Describe No

A

NO is freely diffusible, soluble, lipophilic gas secreted by the endothelium as it is produced (not stored)

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24
Q

What is NO formed by

A

NO formed in the endothelium by calcium sensitive constitutive enzyme endothelial Nitric Oxide synthase (eNOS) from its precursor L-arginine, Tetrahydrobioptern (BH4) is as essential cofactor in this process

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25
Q

What stimulates activation of eNOS

A

Agonist stimulated activation of eNOS followsa rise in inracellular calcium through release from intracellular calcium stores and calcium influx

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26
Q

What is NO production stimulated by

A

Flow stimulayted by both calcium dependent and independent activation of eNOS

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27
Q

Describe the main transcriptional and post-transcriptional mechanisms in response to shear stress

A

Shear stress evokes nitric oxide (NO) production. This is mediated by an increase in eNOS protein activity (1) that occurs within seconds and implicates cytosolic calcium and eNOS protein phosphorylations. Later increases in transcription (2) and eNOS mRNA stability (3) allow to maintain an increased NO production when the stimulus is prolonged

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28
Q

Describe flow sensing mechanical forces in NO production

A

The endothelial cell perceives mechanical tensions such as shear stress through membrane changes and glycoalyx movement which are linked to the cytoskeleton, leading to activation of ion channels that increase Ca2+ permeability. The cytoskeleton is linked to stretch mediated calcium channels

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29
Q

Describe NO mechanisms of action regulating smooth muscle contraction

A

NO increases production of cyclic guanosine monophosphate (cGMP) which acts through a number of mechanisms to reverse vasoconstriction. cGMP-dependent protein kinases (PKGs) elicit multiple phosphorylations of cellular proteins that result in lowering of cellular calcium either through decreased mobilisation from intracellular stores or decreased entry from the extracellular

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30
Q

Summarise NO production and mechanisms of action

A

An increase in calcium in the endothelium results in relaxation (vasodilation). An increase in calcium in muscle results in contraction as calcium stimulates the contraction response in muscle. After smooth muscle has contracted calcium goes back into sarcoplasmic reticulum

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31
Q

What are the targets of endothelial derived nitric oxide

A

Decreased smooth muscle contraction, decreased smooth muscle proliferation, decreased platelet aggregation, decreased LDL oxidation, decreased expression of adhesion molecules. decreased monocyte and platelet adhesion, decreased vasoconstrictor production (endothelin)

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32
Q

What is the function of the endothelium

A

As a monolayer of cells that covers the internal surface of all blood vessels, providing a vast interface between the circulating blood and the vessel wall, the endothelium if involved in many mechanisms of vacular regulation

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33
Q

What mechanisms of vascular regulation is the endothelium involved in

A

Synthesis and release of factors, vascular tone, haemostasis, angiogenesis, permeability, inflammatory response

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34
Q

What diseases are all, in part, causes by endothelial dysfucntion

A

Coronary artery disease, hypertension, stroke

35
Q

Describe a healthy vascular endothelium

A

In a tightly regulated state of balance between pro and antioxidants, vasodilators and vasoconstrictors, pro and anti-inflammatory molecules and pro and anti-thrombotic signals

36
Q

What does a diseased or dysfunctional endothelium lose

A

The tightly regulated balance and displays pro-oxidant, vasoconstrictor, pro-inflammatory and pro-thrombotic properties

37
Q

Describe the effect of oxidative stress on endothelial dysfunction and vascular disease

A

Endothelial oxidative stress reduces the effects of or the bioavailabilty of NO.

38
Q

What may eNOS produce under conditions of substrate or cofactor depletion

A

Superoxide (O2-)

39
Q

When does increased O2- occur

A

In disease associated with diabetes and hypertension

40
Q

What effect does O2- have on nitric oxide

A

Reduces bioavailability of nitric oxide by chemical interaction forming peroxynitrite: Nitric oxide (NO) + superoxide (O2-) -> peroxynitrite (ONOO-)

41
Q

What does peroxynitirite do

A

Interacts with lipids, DNA and proteins triggering cellular responses ranging from modulation of cell signalling to overwhelming oxidative injury

42
Q

Describe the effects of peroxynitirite

A

Modification of mediator pathways and cellular signalling molecules, membrane channel inhibition, impairment of enzyme cofactors, activation (gain of function) of specific enzymes, protein aggregation, cytosolic enzyme inhibition, antioxidant depletion, antioxidant enzyme inhibition

43
Q

Describe how young endothelial cells behave

A

In younger endothelial cells eNOS has adequate cofactor availability e.g. tetrahydrobioprotein (BH4) and produces NO. Reactive oxygen species e.g. superoxide and hydrogen peroxide produced by the mitochondrial electron transport chain (such as NADPH oxidase) are quenches by endogenous antioxidant enzymes (superoxide dismutade (SOD) and catalse)

44
Q

Describe how old endothelial cells behave

A

In older endothelial cells ROS produced in the mitochondria increases NOX mediated O2, this O2 quenches NO bioavailability through conversion of NO to peroxynitrite as well as by uncoupling eNOS via reductions in BH4 availability. In the face of unchanged antioxidant defences these effects lead to a reduction in NO bioavailability and a pro-oxidant phenotype in the aged endothelium

45
Q

What occurs in disease states associated with diabetes and hypertension

A

Similar endothelial oxidative stress and impaired NO bioavailability and a pro-oxidant phenotype in the aged endothelium

46
Q

Explain how vascular changes in hypertension mimic those found in arteries with observed ageing

A

Increased media:lumen ratio, vascular remodelling, increased stiffness, vascular inflammation, calcification

47
Q

Describe the effect of endothelium derived contracting factors

A

Endothelial cells can evoke contraction (constriction) of the underlying vascular smooth muscle cells by releasing endothelium-derived contracting factors (EDCFs), usually prostanoids

48
Q

When are EDCF-mediated responses exacerbated

A

When the production of NO is impaired (e.g. by oxidative stress, ageing, spontaneous hypertension and diabetes)

49
Q

What to EDCFs contribute to

A

Blunting of endothelium-dependent vasodilatations in ages subjects and essential hyperintensive patients

50
Q

Describe how atherosclerosis results in endothelial dysfunction

A

Atherosclerotic plaques occur at specific sites where flow patterns are disturbed. Atherosclerosis typically develops at arterial branches and sites of curvature that are regions of low and disturbed wall shear stress, with complex changes in speed and direction. Continuing work reveals that responses of vascular endothelial cells (ECs) to mechanical stimuli are central to disease initiation and progression

51
Q

What risk factors does atherosclerosis depend on

A

Hyperlipidemia, smoking, hypertension and diabetes

52
Q

Describe laminar blood flow

A

Normal physiologic vascular function and vascular homeostasis, thromboresistance, barrier function

53
Q

Describe disturbed flow

A

Decreased eNOS production, decreased vasodilatation, decreased endothelial cell repair, increased ROS- endothelial permeability to lipoproteins, leukocyte adhesion, apoptosis, SMC proliferation and collagen deposition

54
Q

What is atherosclerosis

A

Chronic inflammatory disease of arteries

55
Q

What does the initiation and progession of atherosclerosis involve

A

Circulatign factors such as LDLs and triglycerides, inflammatory activation of the cells of the vascular wall

56
Q

What happens to LDL in atherosclerosis

A

It undergoes oxidative modifiction within the intima and becomes oxidsed LDL (oxLDL)

57
Q

What do oxLDL and other atherogenic signals lead to

A

Expresssion of adhesion molecules allowing circulating monocytes to attach and migrate into the intima

58
Q

What happens when circulating monocytes migrate into the intima

A

Circulating monocytes differentiate in macrophages

59
Q

What do macrophages do

A

Uptake the oxLDL in order to reduce the lesion and become foam cells

60
Q

What do foam cells do

A

Contribute to the inflammation by releasing pro-inflammatory factors to recruit more leukocytes to the site of the lesion

61
Q

What happens to the lesion in relation to foam cells

A

It progresses and foam cells accumulate becoming apoptotic

62
Q

What happens when foam cells become apoptotic

A

Lipid is deposited and inflammatory signals grow

63
Q

What does the chronic inflammatory response result in

A

Further influx of inflammatory cells

64
Q

What does smooth muscle cell differentiation result in

A

Them to migrate and proliferate from the media into the intima

65
Q

What forms the fibrous cap

A

Proliferated smooth muscle cells in the intima secrete extracellular matrix proteins which form the fibrous cap

66
Q

What are the preferential locations atherosclerosis occurs at

A

Curvatures and bifurications

67
Q

What happens at atherosclerosis hotspots

A

There is a focal region of decreased shear stress around a curvature resulting in decreased eNOS, decreased endothelial repair, decreased cytoskeleton/ cellular alignment in direction of flow, increased reactive oxygen species, increased leukocyte adhesion, increased lipoprotein permeability and increased inflammation

68
Q

What do the factors at atherosclerotic hotspots result in

A

Plaque formation amplifying the region of disturbed flow

69
Q

What are endothelial contracting factors

A

Thromboxane A2, superoxide anion, endothelin-1, angiotensin II, prostanoids, H2O2

70
Q

What are relaxing endothelial factors

A

Adenosine, PGI2, NO, epoxy eicosatrienicacids (EETs), H2O2

71
Q

What is EDHF

A

Endothelial derived hyperpolarisation factor= hyperpolarisation= calcium can’t enter cell= relxation

72
Q

What is EDHF dependent on

A

Gap junctions, it passes through gap junctions

73
Q

Describe the structure of gap junctions

A

Specialised mebrane structures that connect the cytoplasm of adjacent cells. They are intercellular channels, some form gap junction plaques at points of cell-cell contact

74
Q

What is the function of gap junctions

A

Metabolic coupling and electrical coupling

75
Q

Describe metabolic coupling of gap junctions

A

Permit the free passage between cells of small metbolites, nucleoties and 2nd messengers (up to molecular weight on about 1000 daltons, IP3, cAMP)

76
Q

Describe electrical coupling of gap junctions

A

Ions can flow through them gap junctions permit propagation of electrical impulse and change in membrane potential to pass from cell to cell

77
Q

Describe the biological importance of EDHF

A

Inverse relationship between NO and EDHF-type response. Backup role to NO becoming more important in disease states.

78
Q

What dominates in resistance vessels

A

EDHF

79
Q

What are ACh-evoked responses in myometrial arteries during pregnancy dependent on

A

Gap junctions

80
Q

What are EDHF responses mediated by in hypertension

A

Increased EC-SMC coupling

81
Q

What is the mechanism of EDH initiation

A

Similar to NO (increase in endothelial Ca2+) and EDH (not NO) is potentiated by H2O2

82
Q

How is EDHF potentiated by H2O2 a compensatory mechanism in situations where NO bioavailabilty is compromised by increased superoxide production

A

Superoxide is dismutased to H2O2

83
Q

Summarise the endothelium

A

Monolayer forming between the lumen of all blood vessels. Provides vast interface between blood and tissue. Releases vasoactive agents that control numerous functions e.g. vascualr tone, haemostasis. Endothelial dysfunction leads to increase in vascular smooth muscle cotraction (vasospam) and atherosclerosis

Case 4 (7 decks)

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