Vascular Endothelium I Flashcards
VE?
single layer of cells that act as a blood vessel interface
What are the functions of the VE?
vascular tone (secrete and metabolise vasoactive substances)
permeability
thrombostasis (prevent clots, adhere to wall)
absorption/secretion ( allow passive/active transport)
barrier (prevent atheroma, impede pathogen)
growth (mediate cell proliferation)
angiogenesis
inflammation
What are the effects of a vasodilator?
smooth muscle - relaxation - inhibit growth myocytes - increase blood flow - increase contractility platelets - inhibit aggregation
Describe the synthesis of NO
endothelium dependent process
- GPCR stimulated by ACh activated PLC
- converts PIP2 –> DAG + IP3
- IP3 stimulate Ca release which activates eNOS enzyme (also by increased shear stress)
- eNOS mediates reaction of L-arginine + O2 –> L-citrulline + NO
- NO moves into smooth muscle and activates internal guanylyl cyclase to convert GTP –> cGMP
- cGMP activates PKG to stimulate relaxation
How does shear stress affect vessel?
increase flow rate and velocity
increase shear stress and increase friction
stimulate NO synthesis
vasodilation
What is the effect of NO on larger vessels?
smaller
increase diffusion distance
What is the difference between endothelium dependent and flow mediated vasodilation?
ED - ACh stimulates NO production
FM - if vessels occluded, NO release necessary
What are the effects of prostacyclin (PGI2)?
vasodilator
What are the effects of thromboxane (TXA2)
vasoconstrictor
Describe the synthesis of PGI2 and TXA2?
phospholipids --> arachidonic acid (PLA) --> PGH2 (COX1 and COX2) --> TXA2 (thromboxane synthase) --> PGI2 (prostacyclin synthase) COX1 constitutively expressed but COX2 expression induced by inflammatory mediators only
PGH2 –> PGD2, PGE2, PGF2 (pain, fever, inflammation)
What does aspirin target?
COX1 and COX2
Describe the activity of PGI2?
- PGI2 binds to IP1 receptor on smooth muscle
- activates internal adenylyl cyclase
- ATP –> cAMP
- cAMP inhibits MLCK
- reduced cross bridge cycling –> vasodilation
Describe the activity of TXA2?
BASAL
- TXA2 diffused through membrane and binds to TPB receptor
- PLC migrates along membrane and converts PIP2 –> IP3
- IP3 triggers Ca release and up-regulates MLCK
- vasoconstriction
APICAL
- TXA2 binds to TPalpha receptor on platelets
- platelets more active
- produce more TXA2
- positive feedback potentiates response
- platelets aggregate
Where is the core site of TXA2 synthase enzyme?
platelets more than endothelial cells
What is endothelin I (ET-1)?
vasoconstrictor
(can vasodilate depending on the receptor)
minor effect = stimulate growth
What is angiotensin II?
vasoconstrictor
What are antagonists of ET-1?
Agonists?
PGI2, NO, ANP, heparin, HGF, EGF
adrenaline, ADH, AngII, IL-1
What is the mechanism of action of ET-1?
- Agonists/antagonists pass into endothelial cell nucleus
- ECE enzyme converts zymogen (Big ET-1) to ET-1 that is produced by the nucleus
- ET-1 diffuses across basal layer
VASOCONSTRICTION
- ET1 binds to ETA and ETB on VSMC (paracrine)
- converts PIP2 –> IP3
- cause Ca influx
- stimulate MLCK
VASODILATION
- ET1 has autocrine effect
- bind to ETB on endothelial cell
- stimulate eNOS production to make NO for vasodilation
MAJOR EFFECT IS VASOCONSTRICTION
How does angiotensin II work?
via renin-angiotensin-aldosterone axis
- renin cleaves angiotensinogen to Ang I
- ACE converts it to Ang II
- Ang II increases vascular resistance (TPR)
- bind to AT1 receptor to increase water retention
- 3 and 4 increase BP
What is renin?
an enzyme
Where is ACE located ?
on endothelial lining
When is RAA good?
if bleeding to death
maintain circulating volume at adequate BP
What stimulates increased vascular resistance?
arteriolar vasoconstriction
sympathoexcitation
both increase CO –> vasoconstriction
What stimulates increased water resistance?
tubular Na reabsorption
ADH and aldosterone secretion
