Vascular Endothelium Flashcards
What is the vascular endothelium?
Monolayer lining the lumen on blood vessels
What are the 5 functions of the vascular endothelium?
Vascular tone: secretes + metabolises vasoactive substances
Thrombostasis: prevents clots forming and molecules adhering to wall
Absorption and secretion: allows active/passive transport by diffusion/channels
Barrier: prevents atheroma developing and impeding pathogens
Growth: mediates cell proliferation
What is vascular tone homeostasis?
The balance between vasodilating and vasoconstricting forces may be altered to change the radius, altering the resistance to affect flow and blood pressure
What are prostaglandins?
A group of compunds that can effect the vascular tone
Describe prostaglandin synthesis:
Phospholipase A2 catalyses the conversion of membrane phospholipids to arachidonic acid
COX1 and COX2 convert arachidonic acid to the PGH2 (Prostaglandin H2) precursor
Thromboxane Synthase: produces Thromboxane A2 - a pro-platelet vasoconstrictor
Prostacyclin Synthase: produces Prostacyclin - an anti-platelet vasodilator
PGH2 can also be converted to PGD2/PGE2/PGF2 for pain, fever and inflammation
What are the main Vasodilator molecules?
Nitric oxide and Prostacyclin
What are the sources of Nitric oxide?
Exogenous: diffuses from blood to VSMCs (Vascular smooth muscle)
Endogenous: produced in response to ACh/bradykinin binding and shear stress (upregulates eNOS (endothelial nitric oxide synthase))
Describe the synthesis of nitric oxide:
ACh binds to GPCR (G-protein coupled receptor), causing phospholipase C to become activated and move along the membrane, catalysing the conversion of PIP2 to IP3 and diacyl glycerol
IP3 production triggers Ca2+ release from the ER, upregulating eNOS (endothelial nitric oxide synthase)
eNOS converts L-arginine and oxygen to L-citrulline and nitric oxide
What is the mechanism of nitric oxide?
Nitric oxide diffuses to VSMCs, activating guanylate cyclase to convert GTP to cGMP, which upregulates protein kinase G
Protein kinase G activates potassium channels to cause hyperpolarisation and cell relaxation
What are the sources of prostacyclin?
Phospholipids: converted to arachidonic acid via phospholipase A2
PIP2: phospholipase C converts to IP3 and diacyl glycerol which DAG lipase converts to arachidonic acid
How is prostacyclin synthesised?
COX1/2 converts arachidonic acid to PGH2, which is converted to PGI2 (prostacyclin)
What is the mechanism of prostacyclin?
PGI2 diffuses to VSMCs and binds to membrane IP receptors, activating adenyl cyclase to convert ATP to cAMP
cAMP inhibits myosin light chain kinases, causing cell relaxation and vasodilation
What are the main vasoconstrictor molecules?
Thromboxane A2, Angiotensin II and Endothelin I
What is Thromboxane A2?
A vasoconstrictor that activates platelets
What are the sources of Thromboxane A2?
Phospholipase C converts to IP3 and diacyl glycerol which DAG lipase converts to arachidonic acid
What happens when Thromboxane A2 binds to TPbeta receptors?
TXA2 binds to the TPbeta receptors on VSMCs, activating phospholipase C to migrate along the membrane and convert PIP2 to IP3 and DAG
IP3 triggers a Ca2+ influx from the ER which upregulates myosin light chain kinase, causing VSMC contraction and vasoconstriction
What happens when thromboxane A2 binds to TPalpha receptors?
TXA2 binds to TPalpha receptors on platelets, causing them to become active and produce more TXA2 in a positive feedback response
Platelets aggregate for haemostasis
What is angiotensin II produced from, and by what?
AGTI by ACE in lungs
Recall the synthesis of AGTII:
Angiotensinogen produced by the liver and released to the bloodstream
Kidney juxtaglomerular cells release renin in response to decreased blood pressure, sympathetic stimulation or decreased sodium reaching the macula densa cells
Renin catalyses the production of angiotensin I from angiotensinogen
ACE in the lung/kidney vessel endothelial cells converts angiotensin I to angiotensin II and metabolises bradykinin to reduce nitric oxide syntehesis
What are the effects of AGTII?
Increased ADH secretion (more vasoconstriction and water retention)
Increased aldosterone secretion (more sodium absorbed so more water retention)
Increased kidney sodium reabsorption
Upregulated sympathetic system excitation to cause vasoconstriction and increased HR
Arteriolar vasoconstriction
What is the mechanism of AGTII Vasoconstriction?
AGTII migrates through endothelium to VSMC AT1 receptors, binding to activate phospholipase C to convert PIP2 to IP3
IP3 causes Ca2+ influx, upregulating MLCK to cause contraction and vasoconstriction
What is Endothelin I?
Molecule that causes simultaneous Vasoconstriction +++ and vasodilation +
What are the Agonists and Antagonists of Endothelin I?
Agonists: Adrenaline, AGTII, ADH
Antagonists: NO, heparin, Prostacyclin
How is endothelin I synthesised?
Endothelial cell nucleus produces Big Endothelin 1
Endothelin converting enzyme converts to ET1
What is the mechanism of Endothelin I action?
ET1 binds to ETA and ETB receptors on VSMC to activate PLC and produce IP3
IP3 causes Ca2+ influx, upregulating MLCK to cause contraction and vasoconstriction
ET1 binds to ETB receptors on endothelial cells, upregulating eNOS
eNOS increases NO production which diffuses to VSMCs to cause relaxation and vasodilation
What does aspirin do?
Irreversible inhibition of COX enzymes, preventing the conversion of arachidonic acid to PGH2; other NSAIDs are reversible (COX-2 specific only affect COX2)
Describe the mechanism of Aspirin action:
COX-1 constitutively expressed in all cells; acetylation by aspirin inactivates
COX-2 upregulated in physiological insult; acetylation switches function to generate protective lipids
Prostacyclin (anti-platelet vasodilator) produced more in nucleated cells and less so in enucleated platelets, allowing for greater prostacyclin synthase/COX synthesis in endothelial cells; need new platelets to recover function
What are Nitrovasodilator drugs?
Found in GTN sprays, including NO functional group, donating ready to use NO - short acting and drops BP in short term
What are calcium channel blockers?
Effective antihypertensives that prevent IP3 causing a Ca2+ influx to VSMCs, preventing contraction and vasoconstriction
What are ACE inhibitors?
Prevent AGTI from being converted to AGTII to prevent downstream vasoconstriction
Describe the structure of a blood vessel from inside to out:
Lumen: hollow area through which blood may flow
Tunica Intima / Endothelium: one cell thick and allows for exchange and homeostasis/haemostasis
Internal Elastic Tissue
Tunica Media / Smooth Muscle: unconsciously controlled smooth muscle cells
External Elastic Tissue
Tunica Adventitia / Fibrous Connective Tissue: protects the vessel and contains the nerves and blood supply (vasa vasorum) to the vessel
What is the difference between resting and activated endothelium?
Resting Endothelium: is inactivated and anti inflammatory/thrombotic/proliferative
Activated Endothelium: is pro inflammatory/thrombotic/angiogenic
What are the activating factors for the endothelium?
Viruses, smoking, thrombosis, mechanical stress, hypertension, hyperglycaemia, inflammation - chronic activation leads to pro-inflammatory/thrombotic effects
What are the four main activated endothelium processes?
Thrombosis
Senesence
Increased permeability
Leukocyte recruitment
What is senescence of endothelial cells?
Damaged/ageing cells undergo growth arrest to halt proliferation in response to stress/damage; stops damaged cells replicating but cells become pro-inflammatory and contribute to CVD
Describe the increased permeability of the endothelium:
Permeability usually regulated by endothelium, and increased permeability allows plasma protein leakage, and for lipoproteins to pass over and bind to proteoglycans; here they are oxidised before macrophages engulf them to form foam cells
How is leukocyte recruitment achieved?
Integrin present to allow for strong integrin binding
What is Contact inhibition?
When a monolayer of epithelial cells forms and they stop proliferating when they touch, forming tight junctions
What is the pathophysiology of atherosclerosis?
Activation of the endothelium causes leukocytes to strongly adhere and migrate into the sub-endothelial space (endothelial dysfunction)
The activated endothelium becomes more permeable and so lipoproteins diffuse into the sub-endothelial space, bind to proteoglycans and are oxidised; macrophages engulf these to become foam cells (fatty streak formation)
Macrophages accumulated and die to form a necrotic core alongside angiogenesis and senescence (advanced complicated lesion forms)
Where does atherosclerosis tend to occur?
Tends to occur at ranch points where turbulent flow occurs and the blood continuously changes speed and direction
What is the effect of Laminar flow on atherosclerosis?
Activates KLF2/4 transcription actors to upregulate eNOS and anti-inflammatory/thrombotic proteins while also upregulating DNA methyltransferases to allow demethylation of anti-atherotic gene promotor regions and hence increased transcription
What is the effect of turbulent flow on atherosclerosis?
Activates NK-kappaB for pro-inflammatory effects and upreulates DNMT to hypermethylate (repress) anti-atherotic genes
What is angiogenesis?
Formation of new blood vessels from old - essential for embryogenesis, wound healing and menstruation; strongly triggered by hypoxia
What is the angiogenesis paradox?
Angiogenesis leads to plaque growth but also damage due to ischaemia is limited by novel angiogenesis
