Endothelial dervied regulators of vascular homeostasis lecture 8 Flashcards
Summarise the regulation of vascular tone
Vasodilation- NO/EDRF and prostacyclin
Vasoconstriction- endothelin1 (ET-1), thromboxane A2, hydrogen peroxide, superoxide anion
EDRF = endothelial dervied relaxing factor
Describe NO synthesis pathway
3 different enzymes that can make Nitric oxide in the body:
Neuronal NOS (nNOS - type I) - Ca2+ dependant (makes low levels of NOS), Endothelial NOS (eNOS - type III)(makes more NOS), Inducible NOS (iNOS - type II) - immunilogical stimuli (produces high levels of NOS in the body)
NOS act as dimers requiring several factors for full acitvity such as NADPH, BH4
L-arginine converted by hydroxylation then an oxidation coupled by eNOS (regulator) to make NO and L-citruline
Or L-arginine is used in protein synthesis and then degraded in to ADMA and excreted
eNOS- regulation of vascular tone, inhibition of smooth muscle cell proliferation, inhibition of platelet aggregation
Describe the regulators of eNOS activity
Phosphorylation
Association with co-factors- BH4
Cellular location- sequestration by calveolin1 in a less active state
When calcium ions bind, eNOS binds to calmodulin and increases its ativty. Others things bind to eNOS such as hsp90. Akt binds to hsp90 which makes eNOS very active. PKA plays a role in this too
Under shear stress, eNOS will upregulate NO production by ligning themselves in the direction of flow
VEGF stimulates eNOS activity. WEGF and BK activae calcium signalling which increases eNOS activty and active Pi3K which increases eNOS acitivty by Akt/PKB
Describe the activity of NO in vasculature
Freely diffusible gas that acts as a signalling molecule
Local activity- short half-life
Activity limited by circulating haemoglobin alpha
Prevents thrombosis - inihibts platelet adhesion to vessels and activation
Anti-inflammation - inhibits leukyocyte adhesion and migration
Anti-oxidant
Inhibits smooth muscle proliferation and migration
Atheroprotective - prevent atherosclerosis
Once NO diffuses across to smooth muscle, it Activates guanylate cyclase- produces cGMP reduces Ca2+ levels and activates phosphodiesterase, activates PKG which limits activation of the myosin light chain and therefore cross-bridging. Causes relaxation of vessel.
What is the function of prostacyclin on vascular smooth nuclear relaxation?
Phospholipase A2 activity leads to prostacyclin synthesis (rate limiting step)
Cyclooygenases (COX-2 and COX-1) allows formation of prostacyclin through prostaglandin by arachidonic acid. Endothelial cells make prostacyclin synthase thromboxane synthase
Prostacyclin Binds IP receptors (g protein), Activates adenylate cyclase, increasing cAMP conc, activates PKA, Decreases Ca2+ conc limiting smooth muscle contraction. Causing relaxtion of vessel
EDHF also causes vasodilation
Other EC derivded vasodilators are: VEGF produced through heme-oxygenase from breakdown of haem
Endothelial dysfunction and activation
Shift in EC function to reduced vasodilation and more proinflammatory and pro-thrombotic state. Clascially assocaited with reduced bioavailability of NO and reduced vasodilation.
Blood vessles may beomce damaged or leaky with loss of EC.
Endotherlial dysfunction is associated with Hypertension, insulin resistance/diabetes, hear failure, kidney failure, atheroscleorosis.
Markers of endothelial dysfunction are:
INcreased circulating EC dervied soluble adhesion molecules, coagulatio nfactors, reduced NO
What can be a consequence of eNOS uncoupling?
Loss of BH4 uncoupled the eNOS dimer- decreases NO and promotes superoxide generation
Increased NADPH and xanthine oxidase activity increase superoxide production
Peroxynitrite (OONO-) leads to further uncoupling of eNOS after oxidative damage to eNOS and/or BH4
Superoxide produced forms peroxynitrite which is a harmful raical, causing oxidative stress, loss of vasodilation, increased contracticlity and endothelial dysfunction./
Describe vascular complication in diabetes mellitus
Central and peripheral vasculopathies- retinopathy, neuropathy, nephropathy
Increased risk of cardiovascular disease due to plaque rupture find atherothrombosis
Excessive O2- generation in mitochondria intimidates the vascular injury in response to hyperglycaemia
Effects of hyperglycaemia on the blood vessels
in the vessel walls, lots of things happen, the oxidative stress/reduction of arginine will lead to a build up on ADMA and reduction of NO (loss of dilation). The increased inflammation will lead to adhesion of platelets/leukyocytes which release cytokines which will increase inflammation and adhesion and will set up the formation of atherloscrotic plaques. Lipids come into endothelium and inflammatroy cells present will take up the lipid and make foam cells and start forming a atheroma.
What is pre-eclampsia?
Maternal systemic syndrome caused by abnormal placentation in the first trimester
30% associated with intrauterine growth restriction of the foetus
Only cure is the delivery of the placenta
Leads to systemic endothelial activation, systemic inflammatory response, headaches, low platelets, proteinuria, hypertension.
Placenta isnt formed properly and cant provide demand for the embryo causinf hypoxia and oxidative stress. Placenta releases pro imflammatory signals which cause materal endothelial cells dysfuction.
Splice variants of the flt1 gene are produced by the placenta (sFlt-1) and act to bind to VEGF and PIGF and goes to materal circulation and then binds to VEGF so it can no longer react with its cell surface recprotrs. So no longer have cocrrect signalling to get correct levels of eNOS and prostacyclin. Vasodilators decreased and it causes increae in endothelium-1 (vasocontrcitor) which leads to vasoconstriction and hypertension.
