8 - Vascular Endothelium 1

Question 1

What are the three layers of blood vessel walls and what is contained in each layer?

Answer 1

• Tunica intima: endothelial cells
• Tunica media: smooth muscle cells
• Tunica adventitia/externa: vasa vasorum and nerves

Question 2

What are the functions of the vascular endothelium?

Answer 2

• vascular tone: secretes and metabolises vasoactive substances
• thrombostasis: prevent clots forming or molecules adhering to vessel wall
• absorption and secretion: active/passive transport via diffusion/channels
• barrier: prevents atheroma development and impedes pathogens
• growth: mediates cell proliferation

Question 3

What are the constriction antagonists?

Answer 3

• PGI2
• NO
• ANP
• heparin
• HGF
• EGF

Question 4

What are the constriction agonists?

Answer 4

• adrenaline
• ADH
• angiotensin ii
• IL-1

Question 5

What do ACE inhibitors achieve?

Answer 5

• block ACE molecules on endothelial cells
• angiotensin i not converted to angiotensin ii
• angiotensin ii can’t bind to VSMC so no contraction
• bradykinin not broken down (binds to b1 receptor and stimulates NO production)
• vasodilatory effects

Question 6

What are the effects of aspirin on platelets?

Answer 6

• thromboxane made of platelets
• prostacyclin made of endothelial cells
• platelets lack nucleus so can’t replace COX enzymes
• can’t overcome aspirin’s inhibitory effects (thromboxane levels decrease)
• endothelial cells produce more COX enzymes so maintains prostacyclin levels

Question 7

How is arachidonic acid formed and what does it go on to produce?

Answer 7

• formed from phospholipids in membrane (using phospholipase A2)
• cyclooxygenase enzymes (COX1 and COX2) convert it to prostaglandin precursor
• prostaglandin converted into thromboxane A2 using thromboxane synthase
• prostaglandin converted into prostacyclin using prostacyclin synthase
• prostaglandin can be converted into other molecules associated with pain, fever and inflammation

Question 8

What is the mechanism of synthesis and action of NO?

Answer 8

• vasodilator
• acetylcholine binds to GPCR
• PLC (bound to GPCR) migrates along membrane and converts PIP2 to IP3
• IP3 triggers Ca2+ influx from ER
• Ca2+ upregulates eNOS which converts L-arg and O2 to L-cit and NO
• NO diffuses into VSMC and activates guanylyl cyclase
• guanylyl cyclase converts GTP tp cGMP
• cGMP upregulates PKG, which activates K+ channels
• membrane hyperpolarises, the cells relax and vessels dilate

Question 9

What is the mechanism of synthesis and action of prostacyclin?

Answer 9

• vasodilator
• produced by COX 1 and 2
• binds to membrane receptor linked to GPCR
• prostacyclin diffuses into VSMC and binds to IP receptor
• causes upregulation of adenylyl cyclase (which converts ATP to cAMP)
• cAMP inhibits MLCK, reducing cross bridge cycling
• cell relaxes and vessels dilate

Question 10

What is the mechanism of action of thromboxane A2?

Answer 10

• vasoconstrictor
• diffuses through apical basement membrane and binds to receptor on VSMC
• PLC (bound to receptor) migrates along membrane and converts PIP2 to IP3
• Ca2+ influx results from extracellular space and SR
• MLCK up-regulated, causing cell contraction and vessel constriction
• also binds to receptor on platelets
• platelets become active and produce more thromboxane (positive feedback)

Question 11

What is the mechanism of synthesis and action of endothelin-1?

Answer 11

• vasoconstrictor
• endothelial cell nucleus produces endothelin 1 (endothelin converting enzyme activates zymogen)
• ET-1 binds to ETA and B receptors on VSMC
• PLC released which converts PIP2 to IP3
• IP3 triggers Ca2+ influx, the cell contracts and vessels constrict
• also binds to ETB on endothelial cell, upregulating eNOS
• NO production increased, which diffuses into VSMC, causing cell to relax and vessels to dilate

Question 12

What is the renin-angiotensin-aldosterone-system?

Answer 12

• angiotensinogen cleaved to angiotensin i by renin (from kidneys)
• angiotensin i converted to angiotensin ii through ACE enzyme (in lungs)
• increases water retention, vascular resistance and BP

Question 13

What is the mechanism of action of angiotensin ii?

Answer 13

• vasoconstrictor
• AGTii diffuses across endothelium and binds to AT1 receptor on VSMC membrane
• PLC migrates along membrane and converts PIP2 to IP3
• IP3 triggers Ca2+ influx, upregulating MLCK
• causes cell contraction
• ACE metabolises bradykinin which produces NO
• leads to NO mediated vasodilation

Question 14

What does aspirin do?

Answer 14

• causes irreversible inhibition of COX enzymes (inactivates COX1 and switches function of COX2)
• prostaglandin/thromboxane synthesis disabled
• platelets can’t recover