circulation Flashcards
vascular endothelium: recall the structure and function of the vascular endothelium, and recall its role in inflammation
define vascular endothelium
single cell layer of cells (tunica intima) that acts as the blood-vessel interface on top of a basement membrane
5 key physiological functions of vascular endothelium
vascular tone, thrombostasis, absorption and secretion, barrier, growth (and angiogenesis)
key physiological functions of vascular endothelium: vascular tone
secretes and metabolises vasoactive substances
key physiological functions of vascular endothelium: thrombostasis
prevents clots forming or molecules adhering to vessel wall
key physiological functions of vascular endothelium: absorption and secretion
allows active/passive transport via diffusion/channels (regulates flux of fluids and molecules from blood to tissues)
key physiological functions of vascular endothelium: barrier
prevents atheroma development and impedes pathogens
key physiological functions of vascular endothelium: growth
mediates cell proliferation
what are prostaglandins
group of compounds that affect vascular tone
what is the first stage of prostahlandin synthesis
phospholipase A2 catalyses conversion of membrane phospholipids to arachidonic acid
what is the second stage of prostaglandin synthesis
COX-1 and COX-2 convert arachidonic acid to PGH2 precursor
what three compounds can be synthesised from PGH2
thromboxane A2 (pro-platelet vasoconstrictor); prostacyclin (anti-platelet vasodilator); prostaglandins associated with inflammation, pain and fever
2 vasodilator molecules
nitric oxide, prostacyclin
key features of vasodilator molecules
use -yl second messenger in vascular smooth muscle cells and xTP/cXMP to cause vascular smooth muscle cell relaxation and platelet inhibition
exogenous source of nitric oxide
diffuse from blood to vascular smooth muscle cells
endogenous source of nitric oxide
produced in response to Ach/bradykinin binding and shear stress (upregulates eNOS)
nitric oxide: production after ACh stimulation
ACh binds to GPCR → PLC migrates along membrane → converts PIP2 to IP3 → IP3 triggers Ca2+ influx from ER → upregulate eNOS → nitric oxide produced
nitrix oxide: pathway and effect on vascular smooth muscle cells
diffuses into vascular smooth muscle cell → activates guanylate cyclase → upregulates protein kinase G → activates K+ channels, causing hyperpolarisaton, relaxation of cells and vessel dilation
2 sources of prostacyclin
phospholipids (converted to arachidonic acid), PIP2 (phospholipase C converted to IP3 and diacyl glycerol, which is converted by DAG to arachidonic acid)
prostacyclin synthesis
COX-1 or COX-2 convert arachidonic acid to PGH2, which is converted to PGI2 (prostacyclin)
prostacyclin: pathway and effect on vascular smooth muscle cells
PGI2 diffuses into vascular smooth muscle cell → binds to membrane IP receptors → upregulates adenyl cyclase→ cAMP inhibits MLCK → reduced cross bridge cycling, causing relaxation of cells and vessel dilation
3 vasoconstrictor molecules
thromboxane A2, angiotensin II, endothelin I
what does thromboxane A2 do
vasoconstrictor that activates platelets
2 sources of thromboxane A2
phospholipids (converted to arachidonic acid), PIP2 (phospholipase C converted to IP3 and diacyl glycerol, which is converted by DAG to arachidonic acid)
thromboxane A2 synthesis
COX-1 or COX-2 convert arachidonic acid to PGH2, which is converted to TXA2
thromboxane A2: pathway and effect on vascular smooth muscle cells
TXA2 binds to TPB receptor on vascular smooth muscle cell → phospholipase C migrates along membrane → converts PIP2 to IP3 and DAG → IP3 causes Ca2+ to diffuse in → upregulates MLCK → VSMC contracts and the vessel constricts
thromboxane A2: pathway and effect on platelets
TXA2 binds to TPa receptor on platelets → activates and releases more TXA2 (positive feedback) → increased ability to aggregate and stick to endothelium
what is angiotensin II produced by
renin-angiotensin-aldosterone system
basic angiotensin II synthesis
angiotensinogen (liver) → angiotensin I (bloodstream by renin) → angiotensin II (lungs by ACE)
what else does ACE do
metabolises bradykinin to reduce nitric oxide synthesis
5 angiotensin II mechansisms
increase ADH secretion (more vasoconstriction and water retention), increase aldosterone secretion (more Na+ absorbed so more water retention), increase kidney Na+ reabsorption, upregulates sympathetic system excitation to cause vasoconstriction and increase heart rate, arteriolar vasoconstriction
angiotensin II: endothelial pathway and effect on vascular smooth muscle cells
binds to AT1 receptor → PLC migrates along membrane → converts PIP2 to IP3 → IP3 triggers Ca2+ influx from ER → Ca2+ upregulates MLCK → vascular smooth muscle cells contract
what does endothelin I stimulate
majorl stimulation of vasoconstriction, minor stimulation of vasodilation
agonist sources of endothelin I
adrenaline, angiotensin II, ADH
antagonist sources of endothelin I
nitric oxide, heparin, prostacyclin
endothelin-1: production after ACh stimulation
big endothelin 1 produced in endothelial cell nucleus → converted to ET-1 in presence of endothelin converting enzyme
endothelin-1: pathway and effect on vascular smooth muscle cells in presence of agonists
ET-1 binds to ETA and ETB receptors on vascular smooth muscle cells → activates PLC → PIP2 converted to IP3 → Ca2+ influx → cell contracts and vessel constricts
endothelin-1: pathway and effect on endothelial cells and subsequently vascular smooth muscle cells in presence of antagonists
ET-1 binds to ETB receptor on endothelial cells → upregulates eNOS → increased nitric oxide production → nitric oxide diffuses into vascular smooth muscle cells → cell relaxes and vessel dilates
blood vessel structure from lumen to exterior
lumen → tunica intima (endothelium) → internal elastic tissue → tunica media (smooth muscle) → external elastic tissue → tunica adventitia (fibrous connective tissue)
role of lumen
hollow area through which blood flows
roles of tunica intima (endothelium)
one cell thick, allows for exchange and homeostasis, production of: adhesion molecules, matrix molecules, anti-thrombotic or procoagulant factors, vasodilating or vasoconstricting factors, growth factors
features of resting endothelium
inactivated and anti-inflammatory, anti-thrombotic and anti-proliferative
features of activated endothelium
pro-inflammatory, pro-thrombotic and pro-proliferative
activating factors of endothelium
viruses, smoking, thrombosis, mechanical stress, hypertension, hyperglycaemia, inflammation (chronic activation leads to pro-inflammatory and pro-thrombotic effects)
activated endothelium processes
thrombosis, senescence, increased permeability, increased leukocyte recruitment
describe senescence
damaged or aging cells undergo growth arrest to halt proliferation in response to stress or damage
advantage of senescence
stops damaged cells replicating
disadvantages of senescence
pro-inflammatory, contributes to cardiovascular disease
effect of increased permeability
allows plasma protein leakage, and for lipoproteins to pass over and bind to proteoglycans
fate of lipoproteins bound to proteoglycans
oxidised before macrophages engulf them to form foam cells
how is there increased leukocyte recruitment
bind strongly using integrin, not selectin, and transmigrate to tissues in post-capillary venules
increased leukocyte recruitment in large arteries
leukocytes adhere strongly using integrin to endothelium, transmigrate, and become stuck in the subendothelial space
formation of endothelial tight junctions
monolayer that stop proliferating when they touch (contact inhibition), forming tight junctions
