Physiology of the vasculature 1 Flashcards
When do we need to be able to control blood flow?
Exercise- increase supply to muscles and the lungs
Digestion- GI tract needs an increased supply
Thermoregulation- vasodilation= heat loss
Examples of 2 diseases caused by artery wall dysfunction?
Atherosclerosis- initiated by dysfunctional blood vessels
Hypertension- due to blood vessel contraction going wrong
What are the layers of an arterial wall?
Endothelial layer basement membrane internal elastic lamina smooth muscle cells external elastic lamina adventitia (collagen and ECM)
What are the layers of a venous wall?
Endothelial layer
basement membrane
smooth muscle cells
adventitia
What are the main functions of the vasculature?
Supply nutrients
remove waste products
provides gas exchange
What communication occurs between VSMCs and endothelial cells?
endothelial cells produce factors which are released at the basolateral surface and act on the VSMCs
gap junctions between VSMCS- waves of calcium can cross the cells and cause coordinated contraction across the cells
some gap junctions between endothelial cells and VSMCs
What are the features of a healthy endothelium?
have a glycocalyx on the surface of the cells
continuous coating
anti-coagulant lubricant almost
prevents circulating cells from binding to adhesion molecules on the endothelial cell surface
What are the features of an activated/ dysfunctional endothelium?
shedding of the glycocalyx
monocytes binding and interacting with the endothelial cells - can migrate across into the wall
see activated endothelium at sites of disturbed blood flow
activated endothelium attracts neutrophils and monocytes
What signalling occurs in healthy endothelial cells?
N.mitters such as:
Ach, histamine, bradykinin and serotonin bind to receptors
mediates an increase in intracellular calcium
activates endothelial nitrous oxidase synthase (eNOS) to convert arginine to nitrous oxide(NO)
high shear stress also acts to increase NO
What signalling occurs in activated/ dysfunctional endothelial cells?
stimuli such as:
interleukin-1, endotoxin, thrombin and disturbed blood flow act on receptors to:
increase endothelin-1
increase ROS, VCAM-1, IL-8, COX2 activity
Which channels/proteins are involved in keeping intracellular calcium low?
calcium ATPase in the sarcoplasmic reticulum
calcium ATPase in the plasma membrane
Which channels/ proteins are involved in the activation/contraction of muscle cells?
calcium channels in plasma membrane
receptors in plasma membrane coupled to IP3 signalling
calcium channels in sarcoplasmic reticulum
calmodulin
myosin light chain kinase
(myosin phosphatase constitutively active)
What are the contractile stimuli for receptors on the plasma membrane?
Endothelin a/b prostanoids angiotensin 1 histamine noradrenaline
What are examples of calcium channels in the plasma membrane?
voltage sensitive
receptor operated- p2x
TRP channels
store-operated- ora1
What are the key components in VSMC relaxation?
cGMP
cAMP
K channels
How do potassium channels mediate VSMC relaxation?
K efflux leads to hyperpolarisation
this leads to decreased IC Ca
What are the endothelin mediators that regulate VSMC contractility?
Nitric oxide
prostanoids
endothelin-1
angiotensin 2
How does nitric oxide affect contractility?
NO produced from endothelial cells
diffuses to VSMCs
acts on guanylyl cyclase to increase cGMP
increased cGMP activates myosin phosphatase- leading to relaxation
cGMP also decreases IC Ca directly
=relaxation of smooth muscle cells
Where is eNOS located in the endothelial cells?
eNOS is acetylated and complexes with the golgi and caveolae (specialized cholesterol-rich domains in the plasma membrane)
the caveoli structures contain clusters of eNOS enzymes- resulting in NO being produced close to the cell surface
What causes the dysregulation of NO and why?
Smoking- reduces NO bioavailability, also interferes with eNOS acetylation, so there is a loss of eNos anchored at the membrane
Hyperglycaemia- reduction of eNOS phosphorylation, and a reduction in NO bioavailability (mechanisms unclear)
oxLDL- displaces eNOS from the caveolae- disturbs eNOS function
also depletes cholesterol from the caveoli
What is the function of NO?
Regulates blood pressure and regional blood flow
How are prostanoids made?
Prostanoids are produced in the endothelium in response to increased IC Ca or increased ROS production
this activates cyclo-oxygenase 1/2 enzymes which convert arachidonic acid into PGH2
PGH2 can be converted into a number of prostanoid derivatives, depending on the enzymes present
How do the derivatives of PGH2 affect contractility?
Thromboxane A2:
binds to prostanoid TP receptor
this GPCR couples to PLC activation
couples to increases IP3 levels
leads to increased IC Ca and muscular contraction
Prostaglandin E2:
binds to EP-Rs
some EP-Rs activate adenylyl cyclase, others inhibit it
increased cAMP leads to the relaxation response
decreased cAMP leads to the contraction response
Prostaglandin I2:
binds to IP receptors
GPCR receptor couples to activation of adenylyl cyclase
increased cAMP
relaxation response
How is ET-1 made?
Big endothelin is cleaved by endothelin converting enzyme- converting it into ET-1
How does ET-1 affect contractility?
Binds to ETa and ETb GPCR receptors on VSMCs
leads to contraction response
Whats the ET-1 negative feedback loop?
ET-1 acts back on the endothelial cell via ETb receptors
to block ECE activity and increase NO production
=opposes VSMC contraction
endothelial cells only express ETb
How is angiotensin 2 produced?
Angiotensin-converting enzyme (ACE) converts circulating AGT1 into AGT2
How does AGT2 affect contractility?
Binds to AT1 receptors on VSMCs
initiates contraction response and activates MAPK signalling-
that leads to more persistent changes in signalling to make the VSMCs more contractile in their responses
Why does atherosclerosis increase BP?
build up of the plaque physically separates the endothelium from the VSMCs
this results in a loss of coupling between the 2- loss of endothelial regulation of contractility of the artery
thus increased BP
futhermore: increased BP can lead to a loss of elasticity
reinforcing the loss of regulation
