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Physiology of vasculature Flashcards

1
Q

How do we regulate blood supply

A

Vessel relaxation- widening, increases supply

vessel contraction- narrowing, decreases blood supply

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2
Q

Regulating blood supply for organs

A

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

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3
Q

Why do we need to understand the vascular physiology?

A

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

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4
Q

The vasculature of blood vessels

A

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

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5
Q

Why is contraction and relaxation tightly controlled?

A

to regulate blood supply to organs and determine blood pressure

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6
Q

Structure of the artery wall

A

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

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7
Q

What does smooth muscle do?

A

Contracts and relaxes to determine the size of the artery .

mediators released from endothelium and sympathetic nerves

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8
Q

Proximity of endothelium to vascular smooth muscle cells

A

Smooth muscle= thicker

neurones are deeper in the artery to act directly on smooth muscles

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9
Q

Intracellular communication between endothelium and VSMCs

A

release factors that act directly

direct contact between via gap junctions

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10
Q

Gap junctions

A

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

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11
Q

What is the endothelium?

A

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)

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12
Q

Non pathological conditions of the endothelium

A

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
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13
Q

What causes activated/ dysfunctional endothelium?

A
  • injury, injection or inflammation
  • oxLDL (lipid)
  • disturbed blood flow (oscillatory shear stress)
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14
Q

What happens when an endothelium is activated/ dysfunctional? / branched arteries with disturbed flow?

A
  1. Adhesion molecules bind to glycans on circulating blood cells including monocytes, neutrophils and platelets
  2. Glycocalyx shredding
  3. monocyte enters artery wall
  4. initiates/ progresses atherosclerosis
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15
Q

Where does activated endothelium take place?

A

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

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16
Q

Endothelial cell signalling in a healthy endothelium

A

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
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17
Q

Endothelial cell signalling in an unhealthy or activated endothelium

A
  • 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
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18
Q

ET-1

A

released from cells and act adjacent to VSMC

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19
Q

What are VSMC controlled by?

A

intracellular Ca levels- key regulator in contractibility

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20
Q

What happens in resting or relaxed smooth muscles?

A

intracellular Ca is maintained low by Ca ATPase pumps in plasma membrane and SR

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21
Q

What do smooth muscles need to be active?

A

Myosin needs P

Phosphate

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22
Q

How does VSMC Contraction occur?

A

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
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23
Q

How is smooth muscle distinct from skeletal muscle?

A

Smooth muscle myosin mist be phosphorylated to be active

Myosin phosphatase is constitutively active so cell tends to relax in absence of stimuli

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24
Q

What couples to IP3 and what does it do?

A

Second messengers couple to IP3 and cause intracellular Ca to be released and then activation of the myosin phosphorylation contraction pathway

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25
GPCRS
``` endothelium A/B TP (prostanoid) AT1 (angiotensin) histamine noradrenaline (a-AR) ```
26
Calcium channels
``` Voltage sensitive (L type) receptor operated (eg. P2X) TRP channels store operated (Ora1) ```
27
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
28
vascular smooth muscle cell relaxation pathways
1. Nitric oxide- from endothelium- increase cGMP 2. Gs coupled 3. K channel
29
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
30
3 key mediators of relaxation
cGMP cAMP K channels All block Ca
31
Gs coupled pathway?
B agonists, adenosin, prostaglandins | Activates AC which activates cAMP to increase PDE and decrease Ca which causes relaxation
32
K channels
BK channel, SK channels, B agonists K efflux from K channel causes hyperpolarisation which then decreases IC Ca
33
What does PDE do?
hydrolyse 2nd messengers, reduce amount present and reduce relaxation of response
34
What does the endothelium contribute to controlling vascular smooth muscle contraction?
source of many mediators that actively control smooth muscle cell contraction
35
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 ```
36
What results does the EC response have on intracellular signalling in the endothelial cell?
1. some via rise in intracellular Ca 2. signalling is independent of ca (some) 3. gap junctions between endothelium and VSMC allow electrical coupling- level of endothelial hyperpolarisation in resistance vessels
37
4 key endothelial mediators
Nitric oxide pathway proteinoids endothelin angiotensin II
38
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
39
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
40
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
41
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
42
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
43
What happens if you reduce the amount of NO or ENOS?
Raised blood pressure as more contraction
44
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
45
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
46
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
47
Prostanoid derivatives
- Thromboxane (A2) - Prostagladin Es (PGE) - PGI1
48
What does Thromboxane A2 do?
released from EC to act on TP- TPGPCR to PLC activation and IP3 production releases CA muscle contracts
49
Prostagladin E2 (PGE2)
Acts on PGE2 receptors and some EP receptors activate GC increase cGMP= relaxation, decrease cGMP= contraction
50
PGH2
acts on IP receptor on VSMC IPGPCR recptors couple to activate adenylyl cyclase to increase cAMP- relaxation vasodilator
51
What activates PKA
cAMP - then activates myosin phosphatase to mediate relaxation
52
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
53
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
54
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
55
What is ACE?
Predominantly expressed on EC of pulmonary and renal vasculature converts circulating angiotensin I
56
What is AGII?
acts on ATi R on VSMC
57
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
58
Ageing and disease- what goes wrong?
``` Atherosclerosis damage calcification loss of elastin decrease NO- diet, smoking hypoxia ```
59
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
60
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
61
What are diseases which target the vasculature?
- Hypertension - HF - angina - pulmonary hypertension - Raynaud syndrome
62
What is hypertension?
High blood pressure affects 30% of people in England increase risk of MI or stroke
63
Symptoms of hypertension?
breathlessness, fatigue, fluid retention as CO is not adequate to meet metabolic demands
64
Causes of hypertension
most commonly secondary to atherosclerosis
65
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
66
What happens when there is loss of vasodilation?
Hypertension
67
What is heart failure?
Inadequate CO to meet metabolic demands | disease of heart MI or atherosclerosis
68
What is angina?
O2 supply to heart is insufficient upon exertion chest pains due to coronary artery disease
69
What is pulmonary hypertension?
Narrowing of pulmonary arteries increase pressure on right side life expectancy 1-3 years from diagnosis
70
What is Reynard's syndrome?
Inappropriate vasoconstriction of smaller arteries/ arterioles white/ blue fingers to red severe cases- ulceration and gangrene
71
What are primary and secondary Raynaud's?
1. hereditary or idiopathic | 2. connective tissue disorder, obstruction, drug side effects
72
Treatment for Raynaud's?
stop smoking, avoid cold, vasodilator therapies
73
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)
74
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)
75
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 ```
76
ET-1 vasodilators
ETa/b Inhibition= bosentan- prevent hypertension, phase 3 clinical trial, ischaemic optic neuropathy from glaucoma ECE inhibitor= phophoramidon, experimental tool
77
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
78
Directly acting therapies for VSMC? (4)
1. nifedipine= hypertension, raynauds, angina 2. verapramil= hypertension, HF 3. diltrazem= hypertension, angina 4. minoxidil= anti-hypertensive (most commonly used to treat hairloss)
79
What is a PDE inhibitor?
sildenafil= Viagra treats pulmonary hypertension *SHOULD NEVER BE TAKEN WITH NO
80
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
81
Different types of HF treatments?
ACE inhibitiors- Angiotensin II blocker | verapamil- block Ca channel in VSMC
82
What are the treatments for angina?
Nitroglycerine- NO donor diltiazem- Block Ca channels in VSMC Nicorandil- K channel activator and NO donor
83
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

CDL301 (7 decks)

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