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L8 Endothelial Derived Regulators of Vascular Homeostasis
The endothelium regulates vascular homeostasis
Acts as both a sensor and effector:
 Blood flow regulation/vasodilation
 Permeability
 Haemostasis
 Neutrophil/leukocyte recruitment
 Hormone trafficking
Vasodilation
 Nitric Oxide (NO)/EDRF
 Prostaglandin (PGI2)
 EDHF, CO, H2S
Vasoconstriction
 Endothelin-1 (ET-1)
 Thromboxane A2
 H2O2, superoxide anion (O2-)
Endothelial -derived relaxing factor (EDRF)
 Acetylcholine-induced doesn’t occur when the endothelium is removed
 Endothelium produces EDRF
Nitric Oxide Synthases
 Three isoforms ~60% homology – distinct functions in vivo
 Constitutive forms:
o Neuronal NOS (nNOS – type1) – Ca2+ dependent
o Endothelial NOS (eNOS – type III) - Ca2+ dependent
 Inducible NOS (iNOS – Type II) Immunological stimuli
eNOS: cardiovascular EDRF
 Regulation off vascular tone
 Inhibition of SMC proliferation
 Inhibition of platelet aggregation
 Catalyses the sequential hydroxylation and oxidation of L-arginine to produced L-citrulline + NO
 NOW acts as a dimers requiring several cofactors for full activity:
o Heme-iron and BH4
o NADPH (in reduced form – nicotinamide adenine dinucleotide phosphate)
 When NOS doesn’t work properly (e
...
in oxidative stress) ADMA and L-NMMA which are competitive inhibitors
of NOS
Regulation of eNOS activity
 eNOS gene regulation
 eNOS activity
o Phosphorylation
o Association with cofactors – e
...
BH4
o Cellular location – sequestration by caveolin-1 in a less active state
Shear stress and endothelial responses
 Cardiovascular homeostatic mechanisms of flow-mediated dilation
 Endothelium transduces shear stress into a vasorelaxation response via NO
 Shear stress induces eNOS expression & activity
Activity of NO in the vasculature

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Freely diffusible gas that acts as a signalling molecule
Very short half-life 6-30s = local activity
Activity in blood limited by circulating haemoglobin α
Prevents thrombosis – inhibits platelets adhesion to vessels and activation
Anti-inflammatory – inhibits leukocyte adhesion and migration
Antioxidant
Inhibits smoot muscle cell proliferation and migration
Atheroprotective

Relaxation of vascular smooth muscle (vSMC)
 Mechanism of vSMC relaxation
o cGMP reduces [Ca2+]
o regulates phosphodiesterase
o Activates PKG  limit activation of myosin-light
chain kinase (MLCK) essential for myosin-actin
cross bridge formation  smoot muscle
relaxation
Prostacyclin synthesis
 Phosopholipase A2 activity leads to prostacyclin – rate
limiting step – activated by Ca2+ & PKC
 Cyclooxygenases
o COX-2 – inducible
o COX-1 – constitutive (predominant isoform in endothelium)
 Endothelial cells express prostacyclin synthase (PGCIS)
 Platelets use thromboxane synthase to produce thromboxane
Prostacycline (PGI2) and vSMC relaxation
 Prostacyclin binds IP receptors (GPCRs)
o Activates adenylate cyclase
o Increasing (cAMP] activates PKA
o Decreases [Ca2+] limiting vSMC contraction
Endtothelium-derived hyperpolarising factors (EDHF)
 The phenomenon of endothelium-dependent hyperpolarisation and relaxation
 Ach stimulation of artery preparation in the presence of NO scavengers (e
...
haemoglobin) & COX inhibitors
(indomethacin) indication an additional endothelial-dependent vasodilatory activity
 Small molecule with a short half-life
 EDHF effects are blocked with endothelial K+ (e
...
IKca2+) channel inhibitors
 EC become hyperpolarised and signal to vSMCs resulting in hyperpolarisation to produce vasodilation
 EC hyperpolarisation transmitted to myocytes via myo-endothelial gap junctions
OR
 EDHF is K+ exciting EC through K+ channels to activate myocyte K+ channels & Na+/K+ ATPases
Endtothelium dysfunction/activation
 Shift in EC function to reduced vaasodilation & more pro-inflammatory & pro-thrombotic state
 Classically associated with reduced bioavailability of NO & reduced vasodilation
 Blood vessels may become damage and leaky with loss of EC

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Associated with most forms of
Hypertension, Insulin resistance/
diabetes, Coronary artery
disease, Chronic heart failure,
Choronic kidney failure,
Atheroscelrosis, Stroke

Vascular insult – perturbed eNOS
activity
 L-arginine may be metabolsed by
arginase reducing NO synthesis
 eNOS uncoupling: Loss of BH4
cofactor uncouples the eNOS
dimer – decreases NO &
promotes superoxide generation
 NADPH and xanthine oxidase
activity increases superoxide
production
Uncoupling of eNOS in oxidative stress
 Generation of peroxynitrite promotes
oxidative stress
Markers of EC dysfunction
 Increased circulating EC-derived soluble
adhesion molecules: sVCAM-1, slCAM
and sE-selectin
 Coagulaion factors – vWFF, TPA and PAI1
 Proinflammatory signals – CRP, TNFα
 Reduced NO – increased ADMA
 Changes in vasodilator response –
measure of endothelial vasomotor function are predcitive of long-term outcome
 Increased numbers of ciculating endothelial progenitors CEP and microparticles
Vascular complications in diabetes mellitus
 Central and peripheral vasculopathies – retinopathy, neuropathy, nephropathy
 Increased risk of CV disease and copmlication – plaque rupture and atherothrombosis
 Widespread endothelial activation preceds the development of diabetic complications
 Excessive superoxide anion (O2-) generation in mitochondria initiates the vascular injury in respoonse to
hyperglycaemia
Pre-eclampsia (PE)
 Maternal systemic syndrome cause by abnormal placentation in first trimester – clinical symptoms present from
20 weeks onwards
 3-5% of pregnancies in West
 Only cure is delivery of the placenta
 Reduced placental transport
 Altered trophoblast secretions
 Enhanced trophoblast apoptosis
 Increase fibrin deposition
 Systemic endothelial activation
 Systemic inflammatory response

Sypmtoms of pre-eclampisia
 Proteinuria
 Haemolysis
 Elevated liver enzymmes
 Low platelets
 Headaches
 Visual disturbances
 Seizures



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