BIOLOGY 2F03 Lecture Notes - Lecture 6: Guanylyl Cyclase, Bradykinin Receptor, Prostacyclin
19 May 2018
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NORMAL ENDOTHELIAL FUNCTION
1. The endothelium is an organ with a complex structure and a variety of functions
Structure of endothelium
• it is a single flat layer of cells that forms the interface between tissues and blood
• endothelial cells line the entire circulatory system
• cells appear in a cobblestoned morphology in vitro
• cells appear in an aligned morphology in vivo - and this is due to the effect of blood flow/ shear
stress; with cells aligning parallel to flow
• overlaps between cells in vivo occur at junctional areas – this helps them to regulate barrier
function
The endothelium has 5 main functions
• regulation of vascular tone
• barrier function
• pro-inflammatory
• anti-coagulant
• angiogenesis
2. the regulation of vascular tone is achieved by balancing production of vasoconstrictive and
vasorelaxing mediators
The immediate response of the newborn is to upregulate vasorelaxing agents and downregulate
constrictive agents in small pulmonary arteries. failure to do so would result in death
Nitric Oxide has differing effects on endothelial cells and SMCs
• It is produced in endothelial cells from arginine by NOS
• eNOS is constitutively expressed in endothelial cells – it maintains a constant production of NO
o eNOS can be induced by shear stress, O2, ACh and bradykinin
o iNOS is induced in inflammation, nNOS is only produced by neurons
• NO improves endothelial barrier function, growth, motility and promotes angiogenesis (by
promoting VEGF)
• NO diffuses to SMCs to bind to solugble guanylyl cyclase. this produces cGMP which in turn
produces PKG
o Hence NO causes SMC relaxation but inhibits SMC growth and motility
• NO also has anti-inflammatory and anti-thrombotic (platelet adhesion inhibition) effects
Prostacyclin causes cell membrane hyperpolarization
• it is produced in endothelial cells from arachidonic acid via COX
• it elevates cAMP in SMCs. this activates potassium channels and inhibits calcium channels – net
effect is hyperpolarization of the membrane and vasodilation
o it also inhibits SMC proliferation
• Prostacyclin also inhibits platelet aggregation
Natriuretic peptides
• there are 3main types, synthesized in the atria (ANP), brain (BNP) and endothelium (CNP)
• they bind to particulate guanylyl cyclase (not soluble) on SMCs to induce cGMP formation and
achieve vasodilation
• they are stimulated by arterial/ventricular dilation and neurohumoral factors
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