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Human Ageing > Vascular Ageing > Flashcards

Vascular Ageing Flashcards

1
Q

What is vascular ageing, simply?

A

How your blood vessels change as you age = structure and function

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2
Q

When does vascular damage typically start?

A

40s

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3
Q

What happens to people with many risk factors for vascular ageing?

A

Premature vascular ageing

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4
Q

Give examples of risk factors for vascular ageing

A

Modifiable v non-modifiable risk factors

Obesity, diabetes, drugs for cancer, gender

Lifestyle factors = smoking, blood pressure, inactivity, poor diet, stress, lack of sleep

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5
Q

Broadly define cardiovascular disease (CVD)

A

Stroke, coronary artery disease (CAD), heart failure and cardiac arrest

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6
Q

What are non-modifiable risk factores for CVD?

A

Chronological age
Gender
Medical history of CVD or diabetes
Family history of CVD or diabetes

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7
Q

What can vascular dysfunction indicate?

A

Advancing age and may be a precursor to the development of clinical CVDs

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8
Q

What is the microcirculation?

A

Circulation of blood in the smallest blood vessels (capillaries)

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9
Q

What other diseases does the structural and functional alteration of the microcirculation contribute to?

A

Vascular cognitive impairment
Alzheimer’s
Sarcopenia a musculoskeletal disease
Kidney and eye disease

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10
Q

Structure of the aterial layers

A

Tunica intima = endothelium, subendothelial layer and CT basement memrbane
Tunica media = smooth muscle and elastic fibres
Tunica externa = collagen and vasa vasorum

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11
Q

What produces collagen?

A

Fibroblasts are developmentally programmed to produce collagen matrix, which is the main structural component of connective tissue.

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12
Q

Difference between arteries and veins?

A

Veins have a larger lumen, thinner layer of smooth muscle and valves

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13
Q

What is the vasa vasorum?

A

Blood vessels of the blood vessels = small capillaries bringing nutrients to the blood vessels

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14
Q

What else is found in the tunica adventitia?***

A

Nerve fibers and lymphtic vessels

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15
Q

What is the structure of capillaries?

A

Only endothelium and basement membrane
No smooth muscle cells covering these vessel = no contraction

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16
Q

What are the functions of endothelial cells?

A

Semi-permeable membrane = tight junctions allow transport of molecules from blood to tissue

Regulate thrombosis, thrombolysis and platelet adherence = release of factors

Influence vascular tone and blood flow

Regulate immune and inflammatory reactions

Regualte growth of other cell types (SMCs)

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17
Q

Name the two types of SMCs

A

Dedifferentiated (synthetic) SMCs
Differentiated (contractile) SMCs

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18
Q

What is the relationship between the synthetic and contractile SMCs?***

A

SMCs found in different states in blood vessels

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19
Q

What are the features of the dedifferentiated SMC?

A

Proliferating and migrating cells
Non-contractile
Secretory = synthesize extracellular matrix
Rhomboid shape

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20
Q

How do dedifferentiated/synthetic SMCs affect arterial wall?

A

Can cause thickening because they can proliferate
Can move from one layer to another from tunica media to intima

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21
Q

What are the features of the differentiated SMC?

A

Non-proliferating and non-migrating
Contractile
Focal adhesions and integrin receptors connect contractile fibres to ECM
Spindle shape

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22
Q

Why are they called synthetic SMCs?***

A

Because they release factors for making EMC

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23
Q

Most arteries carry oxygenated blood, which don’t?

A

Umbilical and pulmonary arteries

They carry deoxygenated blood to placenta and lungs, respectively

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24
Q

What are the 3 different artery categories, give examples?

A

Elastic arteries = aorta, carotid, common illiac
ac as pressure reservoirs

Muscular arteries = radial, splenic, femoral
Distal to elastic arteies = deliver blood to body organs

Arterioles = found all over the body
Control flow into capillary beds via vasodilation and vasoconstriction

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25
Q

What function and morphological characteristics of arteries alter with age? ***

A

Increased size of large arteries
Blunted angiogenesis
Loss of vascular density
Diminished endothelial glycocalyx

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26
Q

Two specific age-associated arterial phenotypes?

A

Endothelial dysfunction
Arterial stiffening of large elastic arteries

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27
Q

What is disrupted in a dysfunctional endothelium?

A

Loss of homeostasis between oxidants/antioxidants, vasodilators/vasoconstrictors, pro-/anti-inflammatory molecules and pro-/anti-thrombotic signals

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28
Q

What is age-related dysfunction of vascular endothelium defined as?

A

Impairment in flow- or vasodilation

and/or

Reduction in endothelium-derived vasodilator = NO and oxidative stress

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29
Q

Young v Old endothelial cells***

A

In ageing ECs, reduced eNOS expression

Increased iNOS, means NO produced in response to oxidative stress

Excess NO reacts with ROS to form peroxynitrite (ONOO-)

This causes more damage in the cell and makes it dysfunctional

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30
Q

What causes arterial stiffness?

A

Depends on structural elements within the wall = smooth muscle cells, elastin and collagen

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31
Q

What structural and functional changes occur in arterial stiffening?

A

Endothelial function is impaired
Vascular media is thickened

Tunica adventia ECM undergoes remodelling = increased collagen deposition, reduced elastin content, and increased pro-inflammatory cells

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32
Q

What is vascular fibrosis?

A

Vascular fibrosis is the excessive buildup of extracellular matrix components, such as collagen, in the blood vessel walls. It typically results from chronic inflammation, injury, or high blood pressure.

This fibrosis stiffens the vessels, impairing their function, reducing elasticity, and contributing to vascular diseases like atherosclerosis and hypertension.

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33
Q

What happens to elastin with age?

A

Progressive fraying and fragmentation of elastin with age

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34
Q

Can elastin be degraded?

A

Some immune cells can degrade elastin = macrophages and neutrophils
SMCs can produce proteases that degrade elastin

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35
Q

What happens when elastin decreases?

A

We are born with a certain amount of elastin = not synthesized that much

Fibroblasts compensate by making more collagen

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36
Q

What effect does rigid arteries have on our body?***

A

Increased speed at which the pressure wave moves through the system

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37
Q

How is artery wall thickness measured?

A

Carotid intima-media thickness test (CIMT)

Measure non-invasively by ultrasound

38
Q

What is the comparison of male v female carotid intima-media thickness?

A

Men’s overall are thicker
Initially, men’s increased thickness at higher rate
But then after menopause can see women’s shoot up

39
Q

How is arterial stiffness measured?

A

Pulse Wave Veolocity = rate at which pressure waves move down vessels

Blood moves out of LV and into aorta and is pushed through rest of circulatory system
During systole, contraction of LV and ejection of blood into ascending aorta acutely dilates the aortic wall = generating pulse wave that moves along the arterial tree

40
Q

How do you estimate arterial stiffening through measurement of pulse wave velocity?

A

Distance between two measuring sites / time it takes for pulse wave to travel

Carotid-femoral PWV is most used proxy for aortic PWV

41
Q

What mechanic is used to measure PWV?

A

Doppler echocardiography = ultrasound
Magnetic resonance imaging

42
Q

What are the categories of the mechanisms of vascular ageing?

A

Cell-autonomous mechanism
Non-cell autonomous mechanism
That contribute to the phenotype of vascular ageing and age-related pathologies in other organs

43
Q

What are the mechanisms of vascular ageing?

A

Mitochondrial dysfunction
Oxidative stress and inflammation
Reduced NO bioavailability
Genomic/epigenetic alterations
Telomere shortening
Stem cell depletion
Impaired autophagy
Dysregulated nutrient sensing pathways (mTOR and Sirtuins)

44
Q

What contributes to oxidative stress in vascular ageing?

A

NAD(P)H oxidases
Mitochondria

45
Q

What effect does increased ROS have on vascular ageing?

A

Endothelial dysfunction and large elastic artery stiffening

Caused by oxidation of critical proteins and inactivation of endothelium-derived NO

46
Q

What affects age-related reduction in endothelium dependent dilation and enhanced vasoconstriction?

A

Impaired bioavailability of NO
Reduced expression of eNOS

47
Q

What is the reaction product of NO and superoxide in older endothelial cells and arteries?

A

Oxidant peroxynitrite (ONOO-) - highly reactive

48
Q

How does peroxynitrite contribute to vascular ageing?

A

Direct cytotoxic effect
Adverse effects on mitochondrial function
Activation of inflammatory pathways

49
Q

What is inflammaging and criteria describes it?

A

Inflammation in ageing
Chronic, sterile, low-grade inflammation

Sterile = not caused by infection

50
Q

What molecules increase with age-associated sterile inflammation?

A

Increased circulating C-reactive protein (CRP)
Pro-inflammatoy cytokines = TNFa IL-6
Vascular cell adhesion molecule (VCAM-1)

51
Q

What is the correlation of increased CRP and IL-6 in older adults?

A

Positively correlated to aortic stiffness
Inversely related to endothelial dilation

52
Q

What genotype causes an increase in inflammation in aged organisms?

A

Pro-inflammatory shift in gene expression profile of vascular endothelial and SMCs

Contribution of immune cells infiltrating arterial adventitia could be a source of inflammatory cytokines and ROS production

53
Q

What is the role of NFkB in arterial dysfunction in older organisms?

A

Increase in NFkB activity = cause arterial dysfunction

Inhibition improves endothelial dilation and aortic stiffness in older adults

54
Q

What does the pro-inflammatory microenvironment in the vascular wall promote?

A

Vascular dysfunction
Impairs cellular metabolism
Increases apoptosis
Contributes to pathogenesis of vascular diseases

55
Q

What is the cross-talk between vascular inflammation and oxidative stress?

A

ROS act as signalling molecules activating pro-inflammatory signalling pathways (NFkB)

NFkB regulates endothelial activation and expression of pro-inflammatory paracrine mediators

Aged cells have high NFkB
Inhibition of this improves blood flow regulation, decrease systemic inflammation, benefits metabolic effects and extends health span

Inflammatory mediates induce cellular oxidative stress

56
Q

What does TNFa (inflammatory mediator) activate?

A

NAD(P)H oxidases

57
Q

Define cellular senescence and why it occurs

A

Irreversible cell cycle arrest
Tumour suppression and prevents passing damaged DNA to daughter cells

58
Q

When t cellular senescence come about?

A

In response to shortened telomeres
Excessive mitogenic signals
Increased extracellular or intracellular stressors (oxidative stress)
Chromatin disruptions
DNA damage

59
Q

What pathways induce cellular senesence?

A

Tumour suppressor pathways = p53/p21 and
p16/pRB

60
Q

Other name for p53, p21, p16 and pRB?

A

p53 = tumour suppressor protein
p21 = cyclin-dependent kinase inhibitor 1A
p16 = cyclin-dependent kinase inhibitor 2A
pRB = retinoblastoma-like proteins

61
Q

What characterizes senescence?

A

Senescence markers
Senescence-associated secretory phenotype (SASP) = pro-inflammatory & oxidant

Release of classical SASP inflammatory mediators

62
Q

Define SASP

A

Senescence-associated secretory phenotype

63
Q

How is vascular cell senescent spread?

A

Spread of vascular inflammation and oxidative stress from senescent cells to healthy neighbouring cells via SASP

Decreases NO and endothelial function

64
Q

What does mTOR sense?

A

Cellular nutrients, oxygen and energy levels

Inputs from upstream pathways = insulin, IGF-1/2 and AMINO ACIDS

65
Q

What is mTOR and its function?

A

Highly conserved serine/threonine KINASE
Regulates many cellular functions in tissues

66
Q

What are the mTOR signalling complexes known for?

A

mTORC1 = rapamycin sensitive
mTORC2 = less studied in vasculature

67
Q

How is ageing affected by mTOR pathway?

A

Reduced activity = regulate ageing and extend lifespan in invertebrates and mice

Ageing increases mTOR activation in arteries

68
Q

What is mTORs role in SASP?

A

Initiator of SASP = translation of mRNA for IL-1a is increased by mTOR activity

IL-1a is found in senescent cells where it contributes to SASP factors due to positive feedback loop with NFkB

69
Q

What are Sirtuins and their role in ageing?

A

SIRTs = family of transcriptional regulators
Role in longevity and inflammation

70
Q

Where were SIRTs originally discovered?

A

Gene silencing factors in yeast
Sir2 = silent information regulator 2

71
Q

What are SIRTs 1-7 in mammals?

A

NAD+ dependent protein deacetylases

ADP-ribotransferases

72
Q

Where are SIRTS1-4 expressed?

A

SIRTs2-4 expressed in the mitochondria

SIRT-1 expressed mainly in nucleus w some cytoplasmic expression

73
Q

What is the importance of SIRT-1?

A

Deacetylating proteins to adapt gene expression in reponse to cellular energy state

Provides stress resistance by modulation fo pro-inflammatory and oxidative stress pathways via deacetylating histone and non-histone proteins

74
Q

What occurs with age-related reduction of SIRT-1?

A

Endothelial dysfunction because

SIRT-1 reduces oxidative stress, inflammation and pro-apoptotic signalling, DNA damage repair and telomere stability

75
Q

What are the rejuvenation strategies?

A

Caloric restriction
Healthy diet
Elimination of senescent cells
Manipulation of mTOR and SIRT1 signalling
Cell reprogramming

76
Q

What are anti-ageing factors called?

A

Anti-geronic circulating factors governing ageing process

77
Q

Define heterochronic parabiosis

A

Connecting circulatory system of a young and aged organism

78
Q

What part of parabiosis helps rejuvenate endothelial function and microvascular network architecture?

A

Blood factors NOT blood cells
This is proved by injection of young blood plasma into aged mice

79
Q

What is the link between caloric restriction and anti-geronic factors?

A

Aged endothelial cells with sera taken from caloric restricted animal mimics phenotypic effects observed during caloric restriction = anti-inflammatory and pro-angiogenic

Treatment with sera from caloric restricted animals upregualtes SIRT-1

80
Q

What are the methods to eliminate senescent cells?

A

Treat with senolytics
Genetic manipulation and removal of p16 positive cells in aged mice

81
Q

How is genetic manipulation and removal of p16 positive cells in aged mice done?***

A

Senescence cells express high levels of biomarker p16INKN4a

Mouse model expresses binding protein-caspase 8 fusion protein (FK506) = driven by p16INK4a promoter

Cells expressing FKBP-Casp8 fusion proteins = labelled by EGFP

Upon treatment with synthetic compound (AP20187) = causes fusion protein to dimerize and ablate the FKBP-Casp8-expressing cells

82
Q

What does rapamycin do?

A

Rapamycin forms gain-of-function complex with FK506-binding protein to inhibit mTORC1

83
Q

What does inhibition of mTOR via rapamycin impact?***

A

Oxidative stress

Inflammation

Arterial stiffness

84
Q

How can reduced SIRT-1 expression be prevented?

A

Short and long-term caloric restriction

85
Q

What does lifelong transgenic whole-body overexpression of SITR-1 do?

A

Prevent age-related decline in endothelium-dependent vasodilation AND aortic stiffening, slowing its rate with increased age

SIRT-1 modulates NO and endothelial function via deacetylation and subsequent activation of eNOS

86
Q

How does SIRT-1 overexpression prevent adverse structural changes in arteries?

A

Possibly through negative regulation of MMP-9 and/or positive regulation of TIMP-1

Youthful elastin -collagen ratio is maintained in transgenic SIRT-1 overexpressing mice

87
Q

What is NMN and its uses in ageing?

A

A NAD+ intermediate
Shown to increase SIRT-1 activation = reversal of mitochondrial dysfunction in advanced age

Also reverses endothelial dysfunction and oxidative stress in OLD MICE

88
Q

Name a SIRT-1 activator

A

Naturally occuring polyphenol = RESVERATROL

89
Q

What does resveratrol improve?

A

Endothelium-depednent vasodilation in isolated arteries from middle-aged animals

SIRT-1 activator

90
Q

What small molecule is an SIRT-1 activator?

A

SRT-1720 improves endothelial function and reduces inflammation and oxidative stress

These effects are not associated with a restoration of NO

Human Ageing (12 decks)

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