Vascular Ageing Flashcards
What is vascular ageing, simply?
How your blood vessels change as you age = structure and function
When does vascular damage typically start?
40s
What happens to people with many risk factors for vascular ageing?
Premature vascular ageing
Give examples of risk factors for vascular ageing
Modifiable v non-modifiable risk factors
Obesity, diabetes, drugs for cancer, gender
Lifestyle factors = smoking, blood pressure, inactivity, poor diet, stress, lack of sleep
Broadly define cardiovascular disease (CVD)
Stroke, coronary artery disease (CAD), heart failure and cardiac arrest
What are non-modifiable risk factores for CVD?
Chronological age
Gender
Medical history of CVD or diabetes
Family history of CVD or diabetes
What can vascular dysfunction indicate?
Advancing age and may be a precursor to the development of clinical CVDs
What is the microcirculation?
Circulation of blood in the smallest blood vessels (capillaries)
What other diseases does the structural and functional alteration of the microcirculation contribute to?
Vascular cognitive impairment
Alzheimer’s
Sarcopenia a musculoskeletal disease
Kidney and eye disease
Structure of the aterial layers
Tunica intima = endothelium, subendothelial layer and CT basement memrbane
Tunica media = smooth muscle and elastic fibres
Tunica externa = collagen and vasa vasorum
What produces collagen?
Fibroblasts are developmentally programmed to produce collagen matrix, which is the main structural component of connective tissue.
Difference between arteries and veins?
Veins have a larger lumen, thinner layer of smooth muscle and valves
What is the vasa vasorum?
Blood vessels of the blood vessels = small capillaries bringing nutrients to the blood vessels
What else is found in the tunica adventitia?***
Nerve fibers and lymphtic vessels
What is the structure of capillaries?
Only endothelium and basement membrane
No smooth muscle cells covering these vessel = no contraction
What are the functions of endothelial cells?
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)
Name the two types of SMCs
Dedifferentiated (synthetic) SMCs
Differentiated (contractile) SMCs
What is the relationship between the synthetic and contractile SMCs?***
SMCs found in different states in blood vessels
What are the features of the dedifferentiated SMC?
Proliferating and migrating cells
Non-contractile
Secretory = synthesize extracellular matrix
Rhomboid shape
How do dedifferentiated/synthetic SMCs affect arterial wall?
Can cause thickening because they can proliferate
Can move from one layer to another from tunica media to intima
What are the features of the differentiated SMC?
Non-proliferating and non-migrating
Contractile
Focal adhesions and integrin receptors connect contractile fibres to ECM
Spindle shape
Why are they called synthetic SMCs?***
Because they release factors for making EMC
Most arteries carry oxygenated blood, which don’t?
Umbilical and pulmonary arteries
They carry deoxygenated blood to placenta and lungs, respectively
What are the 3 different artery categories, give examples?
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
What function and morphological characteristics of arteries alter with age? ***
Increased size of large arteries
Blunted angiogenesis
Loss of vascular density
Diminished endothelial glycocalyx
Two specific age-associated arterial phenotypes?
Endothelial dysfunction
Arterial stiffening of large elastic arteries
What is disrupted in a dysfunctional endothelium?
Loss of homeostasis between oxidants/antioxidants, vasodilators/vasoconstrictors, pro-/anti-inflammatory molecules and pro-/anti-thrombotic signals
What is age-related dysfunction of vascular endothelium defined as?
Impairment in flow- or vasodilation
and/or
Reduction in endothelium-derived vasodilator = NO and oxidative stress
Young v Old endothelial cells***
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
What causes arterial stiffness?
Depends on structural elements within the wall = smooth muscle cells, elastin and collagen
What structural and functional changes occur in arterial stiffening?
Endothelial function is impaired
Vascular media is thickened
Tunica adventia ECM undergoes remodelling = increased collagen deposition, reduced elastin content, and increased pro-inflammatory cells
What is vascular fibrosis?
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.
What happens to elastin with age?
Progressive fraying and fragmentation of elastin with age
Can elastin be degraded?
Some immune cells can degrade elastin = macrophages and neutrophils
SMCs can produce proteases that degrade elastin
What happens when elastin decreases?
We are born with a certain amount of elastin = not synthesized that much
Fibroblasts compensate by making more collagen
What effect does rigid arteries have on our body?***
Increased speed at which the pressure wave moves through the system
How is artery wall thickness measured?
Carotid intima-media thickness test (CIMT)
Measure non-invasively by ultrasound
What is the comparison of male v female carotid intima-media thickness?
Men’s overall are thicker
Initially, men’s increased thickness at higher rate
But then after menopause can see women’s shoot up
How is arterial stiffness measured?
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
How do you estimate arterial stiffening through measurement of pulse wave velocity?
Distance between two measuring sites / time it takes for pulse wave to travel
Carotid-femoral PWV is most used proxy for aortic PWV
What mechanic is used to measure PWV?
Doppler echocardiography = ultrasound
Magnetic resonance imaging
What are the categories of the mechanisms of vascular ageing?
Cell-autonomous mechanism
Non-cell autonomous mechanism
That contribute to the phenotype of vascular ageing and age-related pathologies in other organs
What are the mechanisms of vascular ageing?
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)
What contributes to oxidative stress in vascular ageing?
NAD(P)H oxidases
Mitochondria
What effect does increased ROS have on vascular ageing?
Endothelial dysfunction and large elastic artery stiffening
Caused by oxidation of critical proteins and inactivation of endothelium-derived NO
What affects age-related reduction in endothelium dependent dilation and enhanced vasoconstriction?
Impaired bioavailability of NO
Reduced expression of eNOS
What is the reaction product of NO and superoxide in older endothelial cells and arteries?
Oxidant peroxynitrite (ONOO-) - highly reactive
How does peroxynitrite contribute to vascular ageing?
Direct cytotoxic effect
Adverse effects on mitochondrial function
Activation of inflammatory pathways
What is inflammaging and criteria describes it?
Inflammation in ageing
Chronic, sterile, low-grade inflammation
Sterile = not caused by infection
What molecules increase with age-associated sterile inflammation?
Increased circulating C-reactive protein (CRP)
Pro-inflammatoy cytokines = TNFa IL-6
Vascular cell adhesion molecule (VCAM-1)
What is the correlation of increased CRP and IL-6 in older adults?
Positively correlated to aortic stiffness
Inversely related to endothelial dilation
What genotype causes an increase in inflammation in aged organisms?
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
What is the role of NFkB in arterial dysfunction in older organisms?
Increase in NFkB activity = cause arterial dysfunction
Inhibition improves endothelial dilation and aortic stiffness in older adults
What does the pro-inflammatory microenvironment in the vascular wall promote?
Vascular dysfunction
Impairs cellular metabolism
Increases apoptosis
Contributes to pathogenesis of vascular diseases
What is the cross-talk between vascular inflammation and oxidative stress?
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
What does TNFa (inflammatory mediator) activate?
NAD(P)H oxidases
Define cellular senescence and why it occurs
Irreversible cell cycle arrest
Tumour suppression and prevents passing damaged DNA to daughter cells
When t cellular senescence come about?
In response to shortened telomeres
Excessive mitogenic signals
Increased extracellular or intracellular stressors (oxidative stress)
Chromatin disruptions
DNA damage
What pathways induce cellular senesence?
Tumour suppressor pathways = p53/p21 and
p16/pRB
Other name for p53, p21, p16 and pRB?
p53 = tumour suppressor protein
p21 = cyclin-dependent kinase inhibitor 1A
p16 = cyclin-dependent kinase inhibitor 2A
pRB = retinoblastoma-like proteins
What characterizes senescence?
Senescence markers
Senescence-associated secretory phenotype (SASP) = pro-inflammatory & oxidant
Release of classical SASP inflammatory mediators
Define SASP
Senescence-associated secretory phenotype
How is vascular cell senescent spread?
Spread of vascular inflammation and oxidative stress from senescent cells to healthy neighbouring cells via SASP
Decreases NO and endothelial function
What does mTOR sense?
Cellular nutrients, oxygen and energy levels
Inputs from upstream pathways = insulin, IGF-1/2 and AMINO ACIDS
What is mTOR and its function?
Highly conserved serine/threonine KINASE
Regulates many cellular functions in tissues
What are the mTOR signalling complexes known for?
mTORC1 = rapamycin sensitive
mTORC2 = less studied in vasculature
How is ageing affected by mTOR pathway?
Reduced activity = regulate ageing and extend lifespan in invertebrates and mice
Ageing increases mTOR activation in arteries
What is mTORs role in SASP?
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
What are Sirtuins and their role in ageing?
SIRTs = family of transcriptional regulators
Role in longevity and inflammation
Where were SIRTs originally discovered?
Gene silencing factors in yeast
Sir2 = silent information regulator 2
What are SIRTs 1-7 in mammals?
NAD+ dependent protein deacetylases
ADP-ribotransferases
Where are SIRTS1-4 expressed?
SIRTs2-4 expressed in the mitochondria
SIRT-1 expressed mainly in nucleus w some cytoplasmic expression
What is the importance of SIRT-1?
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
What occurs with age-related reduction of SIRT-1?
Endothelial dysfunction because
SIRT-1 reduces oxidative stress, inflammation and pro-apoptotic signalling, DNA damage repair and telomere stability
What are the rejuvenation strategies?
Caloric restriction
Healthy diet
Elimination of senescent cells
Manipulation of mTOR and SIRT1 signalling
Cell reprogramming
What are anti-ageing factors called?
Anti-geronic circulating factors governing ageing process
Define heterochronic parabiosis
Connecting circulatory system of a young and aged organism
What part of parabiosis helps rejuvenate endothelial function and microvascular network architecture?
Blood factors NOT blood cells
This is proved by injection of young blood plasma into aged mice
What is the link between caloric restriction and anti-geronic factors?
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
What are the methods to eliminate senescent cells?
Treat with senolytics
Genetic manipulation and removal of p16 positive cells in aged mice
How is genetic manipulation and removal of p16 positive cells in aged mice done?***
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
What does rapamycin do?
Rapamycin forms gain-of-function complex with FK506-binding protein to inhibit mTORC1
What does inhibition of mTOR via rapamycin impact?***
Oxidative stress
Inflammation
Arterial stiffness
How can reduced SIRT-1 expression be prevented?
Short and long-term caloric restriction
What does lifelong transgenic whole-body overexpression of SITR-1 do?
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
How does SIRT-1 overexpression prevent adverse structural changes in arteries?
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
What is NMN and its uses in ageing?
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
Name a SIRT-1 activator
Naturally occuring polyphenol = RESVERATROL
What does resveratrol improve?
Endothelium-depednent vasodilation in isolated arteries from middle-aged animals
SIRT-1 activator
What small molecule is an SIRT-1 activator?
SRT-1720 improves endothelial function and reduces inflammation and oxidative stress
These effects are not associated with a restoration of NO
