Physiology of vasculature Flashcards
How do we regulate blood supply
Vessel relaxation- widening, increases supply
vessel contraction- narrowing, decreases blood supply
Regulating blood supply for organs
Exercise- increases supply to muscles, lungs and heart
digestion- increases supply to GI tract
Thermoregulation 1. vasoconstriction and 2. vasodilation- heat loss across the epidermis
capillaries dilate further away from the body to get heat loss
Why do we need to understand the vascular physiology?
arterial contraction/ relaxation results in changes in blood pressure
artery wall dysfunction underlies diseases
- atherosclerosis- initiated by dysfunctional blood vessels
- hypertension- high blood pressure due to vessel contraction
The vasculature of blood vessels
vein- adentia, smooth muscle, endothelium and then lumen most inside
Artery- the same- strong as they supply with blood pumping away from the heart, contract and relax
arterioles- come off arteries
Smaller muscular arteries and arterioles are the main resistance vessels
vein= resupply blood back to heart
Why is contraction and relaxation tightly controlled?
to regulate blood supply to organs and determine blood pressure
Structure of the artery wall
Outside to inside
tunica externa- strong fibrous tissue to maintain blood vessel shape
elasticity
tunica media- contains smooth muscle, elastin, collagen matrix
tunica intima- connective tissue
endothelium- thin layer of cells in direct contact with the blood
What does smooth muscle do?
Contracts and relaxes to determine the size of the artery .
mediators released from endothelium and sympathetic nerves
Proximity of endothelium to vascular smooth muscle cells
Smooth muscle= thicker
neurones are deeper in the artery to act directly on smooth muscles
Intracellular communication between endothelium and VSMCs
release factors that act directly
direct contact between via gap junctions
Gap junctions
between smooth muscle cells, physically coupling
Allow effective waves of calcium signalling across many cells so that the artery wall contracts in a coordinated way
What is the endothelium?
Line every blood vessel
target organ surface covers > 1 football pitch
Health endothelium= healthy CV system
Unhealthy or activated Endothelium= disease- critical in the first changes that take place to cause disease (dysregulating BO and initiating events underlying atherosclerosis and thrombosis)
Non pathological conditions of the endothelium
Glycocalyx
- intact in nonactivation endothelium
- anti-coagulant- form continuous coating
- lubricant that stops circulating cells from binding to adhesion molecules on endothelial surfaces
- consists of carbohydrates and sugar chains protruding from the apical surface of the endothelium
What causes activated/ dysfunctional endothelium?
- injury, injection or inflammation
- oxLDL (lipid)
- disturbed blood flow (oscillatory shear stress)
What happens when an endothelium is activated/ dysfunctional? / branched arteries with disturbed flow?
- Adhesion molecules bind to glycans on circulating blood cells including monocytes, neutrophils and platelets
- Glycocalyx shredding
- monocyte enters artery wall
- initiates/ progresses atherosclerosis
Where does activated endothelium take place?
At sites of disturbed blood flow
branches and bends in the artery
straight vessels- blood flow exerts an event of shear stress force against the well
branched= disturbed
Endothelial cell signalling in a healthy endothelium
stimulated by neurotransmitters such as Ach, histamine, 5-HT and bradykinin
- bind to various receptors to mediate an increase in IC ca
- activate eNOS to convert argine to NO and citrulline
- High shear stress which occurs in straight arteries- increase NO
Endothelial cell signalling in an unhealthy or activated endothelium
- stimuli activates EC- interleukin-1, endotoxin ( bacteria in cell wall) and thombin (from platelets)
- disturbed flow act on ROS, ICAM-1, VCAM-1(adhesion molecules),il3 and cox2 to increase
- increased adhesion molecule expression and shredding of glycocylax
- leads to increased monocyte, neutrophil and platelet interactions
ET-1
released from cells and act adjacent to VSMC
What are VSMC controlled by?
intracellular Ca levels- key regulator in contractibility
What happens in resting or relaxed smooth muscles?
intracellular Ca is maintained low by Ca ATPase pumps in plasma membrane and SR
What do smooth muscles need to be active?
Myosin needs P
Phosphate
How does VSMC Contraction occur?
Second messengers can increase ca intracellular levels by activating release from SR stores
This leads to binding by calmodulin to form a complex (Ca-CaM)
- This activates myosin light chain kinase which phosphorylates myosin cause activation (MLCK)+P
- actin cross bridge cycle starts= contraction
How is smooth muscle distinct from skeletal muscle?
Smooth muscle myosin mist be phosphorylated to be active
Myosin phosphatase is constitutively active so cell tends to relax in absence of stimuli
What couples to IP3 and what does it do?
Second messengers couple to IP3 and cause intracellular Ca to be released and then activation of the myosin phosphorylation contraction pathway
GPCRS
endothelium A/B TP (prostanoid) AT1 (angiotensin) histamine noradrenaline (a-AR)
Calcium channels
Voltage sensitive (L type) receptor operated (eg. P2X) TRP channels store operated (Ora1)
What activates these pathways?
GPCR activate these pathways.
Different types of Ca channels- voltage, storage, Receptor
Different types of pathways that act to increase intracellular ca
vascular smooth muscle cell relaxation pathways
- Nitric oxide- from endothelium- increase cGMP
- Gs coupled
- K channel
What is the nitric oxide pathway?
Nitric oxide to GC(guanylyl cyclase) which activates cGMP and the activates PKG which activating PDE
- Decreases Ca
- increases myosin phosphatase
3 key mediators of relaxation
cGMP
cAMP
K channels
All block Ca
Gs coupled pathway?
B agonists, adenosin, prostaglandins
Activates AC which activates cAMP to increase PDE and decrease Ca which causes relaxation
K channels
BK channel, SK channels, B agonists
K efflux from K channel causes hyperpolarisation which then decreases IC Ca
What does PDE do?
hydrolyse 2nd messengers, reduce amount present and reduce relaxation of response
What does the endothelium contribute to controlling vascular smooth muscle contraction?
source of many mediators that actively control smooth muscle cell contraction
What is the top of EC in contact with and what does it respond to?
in contact with blood (apical surface) responds to: 1. circulating hormones 2. thrombin from platelets- injury 3. cytokines and infectious stimuli- inflammation/ immune response 4. shear stress
What results does the EC response have on intracellular signalling in the endothelial cell?
- some via rise in intracellular Ca
- signalling is independent of ca (some)
- gap junctions between endothelium and VSMC allow electrical coupling- level of endothelial hyperpolarisation in resistance vessels
4 key endothelial mediators
Nitric oxide pathway
proteinoids
endothelin
angiotensin II
Mechanism of nitric oxdide derived vasodilator
1980- endothelial derived relaxing factor
NO regulates blood pressure and regional blood flow
vasodilators act to increase NO production
GPCR couple and cause increase in IC ca calmodulin-n responsible for NOS
- NO activates GC which increases cGMP and causes relaxation
Where is NO produced?
in the epithelium in response to increase in Ca IC
released from endothelial cells after production- freely permeable and diffuses to act on VSMC
What is an additional regulatory mechanism of NO?
regulatory at the P of specific residues of ENOS
regulate sensitivity to calcium calmodulin
shear stress regulates ENOS
How does NO affect the VSMC
NO relaxes smooth muscle by acting on guanylyl cyclase to increase cGMP
increase cGMP activates PKG which activates myosin on phosphatase
leading to relaxation
cGMP also decreases IC Ca directly
how is nitric oxide dysregulated?
By the same factors as CVD
- smoking= reduces NO bioavailability
- high glucose and insulin= less ENOS P
- ocLDL- depletes cholesterol from caveolae- loss of ENOS
What happens if you reduce the amount of NO or ENOS?
Raised blood pressure as more contraction
How does oxLDL affect Blood pressure?
displaces eNOS from caveolae
hypercholesterolaemia
means that NO production is dysregulated leading to loss of ability to regulate blood pressure- increased hypertension
ENOS with caveoli
ENOS is acetylated and complexes with the Golgi and caveolae
caveolae structures contain clusters of eNOS enzymes
result in NO being produced
act rapidly on VSMC
Mechanism of action of Endothelial derived prostanoids?
prostanoids- produced in endothelium in response to increase Ca or ROS
- activates cyclo-oxygenase 1/2 enzymes to convert arachidonic acid to PGH2
- PGH2 - converted to number of prostanoid derivatives
Prostanoid derivatives
- Thromboxane (A2)
- Prostagladin Es (PGE)
- PGI1
What does Thromboxane A2 do?
released from EC to act on TP- TPGPCR to PLC activation and IP3 production
releases CA
muscle contracts
Prostagladin E2 (PGE2)
Acts on PGE2 receptors and some EP receptors
activate GC
increase cGMP= relaxation, decrease cGMP= contraction
PGH2
acts on IP receptor on VSMC
IPGPCR recptors couple to activate adenylyl cyclase to increase cAMP- relaxation
vasodilator
What activates PKA
cAMP - then activates myosin phosphatase to mediate relaxation
endothelial derived endothelium ET-1
Precursor of ET-1 is big endothelium which is regulated by a variety of stimuli (inflammatory or pathogenesis)
- endothelium enzyme cleaves to ET-1
- ER-1 released from EC to act on VMCS at both ETA and B GPCR Gp receptors
- this couples to contraction response via PLC and IP3
What is the negative feedback mechanism of of ET-1
ET-1 acts back on EC via ETB receptors to block ECE activity
and increases NO
oppose contraction
What does the endothelium express? Why is this important?
only expresses ETB not a
Of interest therapeutically as we may wish to specifically block ETA receptors NOT etB
What is ACE?
Predominantly expressed on EC of pulmonary and renal vasculature converts circulating angiotensin I
What is AGII?
acts on ATi R on VSMC
What is AT1
activates MAPK pathway in VSMC leading to persistent changes in signalling to make more contractible in their response
long term effects on smooth muscle
Ageing and disease- what goes wrong?
Atherosclerosis damage calcification loss of elastin decrease NO- diet, smoking hypoxia
What happens during atherosclerosis?
Build up of plaque in arteries
means the endothelium is more separate from VSMC
loss of coupling between them
- loss of contractibility of artery
- results in raised blood pressure
- more strain on arteries
- loss of elasticity and can reinforce loss of function
What causes damage to the glycocalyx?
- hyperglycaemia- excessive insulin dampens akt effect on eNOS
- hyperlipidaemia- deplete cholesterol from endothelial caveoli, reduce function of eNOS + atherosclerosis
- smoking- reduceds NO bioavailability
- sepsis and inflammation- activates leukocytes to artery wall- weakens atherosclerotic plaque
What are diseases which target the vasculature?
- Hypertension
- HF
- angina
- pulmonary hypertension
- Raynaud syndrome
What is hypertension?
High blood pressure
affects 30% of people in England
increase risk of MI or stroke
Symptoms of hypertension?
breathlessness, fatigue, fluid retention as CO is not adequate to meet metabolic demands
Causes of hypertension
most commonly secondary to atherosclerosis
risk factors to damage to vascular function
Smoking- damage glycocalyx, reduce NO bioavailability
hyperlipidaemia- reduced eNOS, fatty plaques
hyperglycaemia- insulin dampens akt effect on eNOS, damage glycocalyx and increased endothelin production (vsmc contraction)
ageing- loss of elastin
infection- leukocytes recruited
high sodium- reduced NO
What happens when there is loss of vasodilation?
Hypertension
What is heart failure?
Inadequate CO to meet metabolic demands
disease of heart MI or atherosclerosis
What is angina?
O2 supply to heart is insufficient upon exertion
chest pains
due to coronary artery disease
What is pulmonary hypertension?
Narrowing of pulmonary arteries
increase pressure on right side
life expectancy 1-3 years from diagnosis
What is Reynard’s syndrome?
Inappropriate vasoconstriction of smaller arteries/ arterioles
white/ blue fingers to red
severe cases- ulceration and gangrene
What are primary and secondary Raynaud’s?
- hereditary or idiopathic
2. connective tissue disorder, obstruction, drug side effects
Treatment for Raynaud’s?
stop smoking, avoid cold, vasodilator therapies
What is the drug target for these diseases?
Vasculature
most therapies= vasodilators requiring relaxation of VSMC
Therapies act on 4 endothelial mediator (NO, ET-1, prostanoids, angiotensin II)
Endothelial derived vasodilators- nitric oxide donors
nitroglercine= converts into NO by mitochondrial aldehyde dehydrogenase- spray
sodium nitroprusside= emergency hypertension- injection
inhaled NO= pulmonary hypertension (server)
Prostamoid vasodilators
Iloprost= PG1/2- pulmonary hypertension or Raynaud's - inhaled or IV Epoprostenol= IP receptor agonist, same uses in pulmonary hypertension Corticosteroids= supresses formation of prostagldins, prevent shock
ET-1 vasodilators
ETa/b Inhibition= bosentan- prevent hypertension, phase 3 clinical trial, ischaemic optic neuropathy from glaucoma
ECE inhibitor= phophoramidon, experimental tool
Angiotensin II vasodilators
ACE inhibitors= hypertension, HF and after MI
types:
- captopril- side effects: hypotension, cough, proteinuria, weird taste
- enalapril- require conversion to active metabolite, longer acting
AT1 receptor antagonists
- blood pressure reduction
sartans- lostartan, valsartan
- inhibit production of angiotensins at renin-angiotensin-aldosterone system
Directly acting therapies for VSMC? (4)
- nifedipine= hypertension, raynauds, angina
- verapramil= hypertension, HF
- diltrazem= hypertension, angina
- minoxidil= anti-hypertensive (most commonly used to treat hairloss)
What is a PDE inhibitor?
sildenafil= Viagra
treats pulmonary hypertension
*SHOULD NEVER BE TAKEN WITH NO
What are the different types of hypertension treatments
sodium nitropusside- NO donor
ace inhibitor- Angiotensin II
Sartans AT1 receptor on VSMC
Nifedipine, verapamil and dilitiazem- Ca channel blockers
Minoxidil, diaxoxide- K channel activators in VSMC
Different types of HF treatments?
ACE inhibitiors- Angiotensin II blocker
verapamil- block Ca channel in VSMC
What are the treatments for angina?
Nitroglycerine- NO donor
diltiazem- Block Ca channels in VSMC
Nicorandil- K channel activator and NO donor
What are the treatments for hypertension?
Inhaled NO- No on vsmc
Iloprost- prostacyclin, increase cAMP in VSMC
Bosentan- ETa/b antagonist- blocks IP3 mediates Ca release
Sildenafil (Viagra) - phosphodiesterase inhibitor, stops cAMP and cGMP hydrolysis
