Regulation of Blood Flow and Blood Pressure Flashcards
- Describe the structure of a blood vessel and identify the cellular components - Understand the mechanisms by which the body can regulate blood flow and pressure - Discuss the key signalling pathways involved in vascular function and explain how these go wrong in disease - Explain current pharmacological strategies to improve vascular reactivity and blood flow
The function of blood vessels
Carry blood around the body towards target organs and tissues
Systemic arteries, arterioles and capillaries
carry oxygenated blood and nutrients from left ventricle towards systemic organs
Systemic veins, venules, and capillaries
deoxygenated blood and waste from periphery towards the right atria
Pulmonary blood vessels
- reoxygenation of blood at the lungs
- returned to heart for circulation
function of intima (endothelial cells and subendothelial space)
- single-cell layer
- first barrier to pathogens in the blood
- communicates with vascular smooth muscle to regulate diameter
function of the media (vascular smooth muscles)
relaxation/constriction dictates vessel diameter
Adventitia/externa
- outer layer of fibrous connective tissue surrounding an organ
- collagen rich
- external elastic lamina
- vaso vasorum
Vessel diameter
regulates blood flow and pressure
Layers of arteries and arterioles
intimal, medial, and externa elastic
Function of valves
Prevent backflow of blood
Difference between veins and arteries and arterioles
veins and venules lack elastic layers
Key hormones in regulation of vasular tone
- nitric oxide
- endothelial derived hyperpolarising factor
- endothelin-1
- angiotensin II
Production of nitric oxide
- stimulation of GPCR by ligand creates multiprotein cascade
- production of IP3 which acts on the ER to singal release of intracellular calcium
- calmodulin activation -> phosphorylation and activation of nitric oxide synthase (ENOS)
- ENOS catalyses the conversion of L-Argenine to L-Citruline
How does nitric oxide cause smooth muscle contraction
- activation of guanylyl cyclase
- converts GTP to GMP
- activation of PKG
- relaxation of muscle fibres
Endothelial derived hyperpolarising factor (EDHF)
- hyperpolarises smooth muscle via stimualtion of potassium efflux
- muscle relaxation
- important when NO production is compromised
- acts predominantly at the arteriole level
Endothelin-1
- acts on smooth muscle to induce vasoconstriction via smooth muscle intracellular calcium release
- inhibits eNOS
- reduces NO bioavailability
- promotes vascular inflammation
Angiotensin II
- multiple tissue targets
- smooth muscle constriction via GPCR signalling and intracellular calcium release
- excessive levels promote high blood pressure and vascular inflammation
Metabolic syndrome diagnostic criteria
- insulin resistance
and any two of: - obesity
- dyslipidaemia
- raised blood pressure
- raised blood glucose
Atherosclerosis
progressive thickening and hardening of medium to large sized arteries as a result of fat deposition on the inner lining
5 key stages of atherosclerosis
- endothelial dysfunction
- immune cell infiltration
- fatty streak
- young plaque
- unstable plaque
Endothelial dysfunction
- can be measured as indicator of atherosclerosis risk
- begins in response to cardiovascular risk factors and chronic inflammation
- loss of endothelium-derived vasomotor control (decreased NO production, increased ET-1)
Characterised by
- increased expression of adhesion molecules
- increased chemokine and cytokine secretion
- increased cell permeability
- increased LDL oxidation
Immune cell infiltration
- infiltration of the sub-endothelial space by immune cells and ox-LDL
Characterised by
- increased adhesion molecules present on endothelial cells
- initial recruitment of monocytes/macrophages
- followed by other immune cells (T and B cells, neutrophils and dendritic cells)
Fatty streak
- further accumulation of ox-LDL and phagocytosis of ox-LDL by macrophages
- visible as yellow fatty streak on vessel lumen
- lipid droplets form in vascular smooth muscle cytoplasm
- smooth muscle and fibroblast proliferation and migration
- dysregulated signalling of ET-1, NO, and Ang-II
Young plaque
- accumulation of ‘foam cells’ and thinning of fibrous cap
- foam cells cluster, creating hypoxic central core (becomes neurotic)
- fibrous cap of developing plaque thins as lesion grows
- plaque is stable but narrowing vessel lumen
Vulnerable/unstable plaque
- plaque becomes unstable
- necrotic core
- calcification
- likely to rupture, releasing thrombus and occluding vessel
How does adipocyte dysfunction promote atherosclerosis
- hyperinflammatory adipocytes release pro-inflammatory cytokines and adipokines
- contribute alongside: insulin and leptin resistance, increased FFA, and hypercholesterolaemia
Dysregulation of AngII in MetS
- increased levels and signalling
- promotes inflammation and smooth muscle proliferation, resulting in atherogenic environment
Dysregulation of ET-1 in MetS
- potent inflammatory peptide - promotes oxidative stress and immune cell recruitment in vessel wall
- increased production and processing also supresses NO signalling, promoting vasoconstriction
Dysregulation of NO in MetS
bioavailability of NO reduced via inhibition of eNOS and peroxinitrate production
Dysregulation of EDHF in MetS
decreased production and transport of EDHFs, impairing vascular responses
MetS and CVD
- pathophysiology of CVD and MetS is multifaceted
- wide array of therapies to treat insulin resistance, inflammation, oxidative stress, cholesterol, hyperglycaemia, hypertension
Common therapies for MetS and Atherosclerosis
- Thiazolidinediones (TZDs/Glitazones)
- HMG-CoA Reductase Inhibitors (Statins)
- AMPK activators (Biguanides)
- Antioxidants
Thiazolidinediones (TZDs/Glitazones)
PPARy agonists
- insulin sensitisers
- increases HDL cholesterol
- anti-inflammatory effect in vessel wall
HMG-CoA Reductase Inhibitors (Statins)
cholesterol biosynthesis inhibitors
- increases HDL cholesterol levels
- decreases LDL cholesterol levels and oxidation
AMPK activators (Biguanides)
complex I inhibition
- regulates glucose metabolism
- increases FA oxidation
- reduces inflammation
Antioxidants
- reduce ROS
- reduce LDL oxidation
Current therapies for vascular dysfunction
- NO donors
- ACE inhibitors
- Endothelin receptor antagonists
- Endothelin converting enzyme (ECE) inhibitors (currently untested in humans)
- Surgery
NO donors
Improves vasoresponsiveness
ACE inhibitors
- reduces AngII production
- alleviates vasoconstriction / favours vasodilation
- reduces blood pressure
Endothelin receptor antagonists
limited effectiveness
