Physiology of the vasculature Flashcards
Give three causes of hypertension
Secondary to CHD
Volume overload in circulation (Valve defects)
Pressure overload (narrowed valves or pH)
What is Raynaud’s disease
Inappropriate vasoconstriction of smaller arteries/ arterioles
White, then blue fingers, then redness due to reactive hyperaemia after return of blood flow.
Severe cases cause ulceration and gangrene
Treated with vasoactive therapies
Give the structure of the artery wall
Tunica externa, media and intima
Smooth muscle sits within the tunica media.
What is the importance of endothelium in heart disease
Dysfunctional/ activated endothelium lead to CV disease.
What is the glycocalyx
Layer on top of the endothelium made up of carbohydrate chains that stick out. These act to prevent cells adhering to molecules on the endothelial surface.
How is the glycocalyx implicated in activated/dysfunctional endothelium
Results in glycocalyx shedding, this is an important response for inflammation and healing. It also represents the initial stage of atherosclerosis
Monocytes are able to bind and translocate across the epithelium. Once inside the artery wall they begin engulfing lipids and initiating atherosclerosis.
It also disturbs blood flow
Outline the steps of vascular smooth muscle contraction
Rapid Ca influx, Ca interacts with calmodulin which activates mysoin light chain kinase (MLCK)
MLCK phosphorylates inactive myosin which can then interact with actin leading to crossbridge formation and contraction.
Myosin phosphatase inactivates myosin
in smooth muscle myosin needs to be phosphorylated to be active and the phosphatase is always active.
What alternative ways are there to cause smooth muscle contraction
Receptors that activate 2nd messengers like IP3, these act on channels at the SR and cause Ca depletion from intracellular stores.
Give 5 non calcium channel receptors that increase Ca
Endothelin A/B
TP (Prostanoid)
AT1 (Angiotensin)
Histamine
Noreadrenaline
All are GPCRs
Give 4 examples of calcium channels
Voltage senstive (L-type)
Receptor operated (P2X)
TRP channels
Store operated (Ora1)
How do K channels induce relaxation and give examples
K channels lead to K efflux which hyperpolarises the cell.
Hyperpolarisation reduces intracellular calcium. Calcium no longer activates MLCK - No active myosin so relaxation of smooth muscle.
Eg BK channels, SK channels, B-agonists (via By -G protein)
How do Gs coupled receptors lead to smooth muscle relaxation and give examples
Gs coupled receptors lead to an increase in cAMP via adenylyl cyclase. High intracellular cAMP reduces Ca conc. Again this leads to a reduction in activated MLCK, then activated myosin
How does nitric oxide lead to relaxation of cmooth muscle
Nitric oxide freely diffuses into smooth muscle and activates guanylyl cyclase, this increases cGMP which activates PKG.
PKG can directly inhibt the conc of intracellular Ca
OR it can activate myosin phosphatase which will inactivate MLCK
What role does PDE have in smooth muscle relaxation
PDE hydrolyses cAMP and cGMP. If it was to do so then relaxation would be inhibited (PDE inhibitors can be used for this reason)
Where is eNOS located
Epithelial cell caveolae
What 3 mechanisms inhibit eNOS
- Smoking
- High glucose/ insulin: Insulin signalling activates AKT which phosphorylates eNOS, loss of IRS therefore causes dysregulation of NO
- oxLDL depletes cholesterol from caveolae. This leads to a loss of eNOS
The overall effect of these is to increase BP
How do endothelial derived prostanoids regulate smooth muscle contraction
ROS or increased calcium in endothelia activate COX1/2 activity.
This leads to an increase in the conversion of arachidonic acid to prostaglandin H2. PGH2 is the precursor to 3 proteins
- ThromboxanA2
- PGE2
- PGI2
These have effects on vascular smooth muscle receptors.
How does PGI2 (prostacyclin) regulate smooth muscle contraction
Acts on IP-R which activates AC leading to increased intracellular cAMP and relaxation
How does PGE2 regulate vasoconstriction
Acts on EP-R (1-4) depending on which EP-R it binds depends on if it activates or inactivates the production of cAMP
How does TxA2 regulate vasoconstriction
Acts on the TP receptor which induces PLC activation. This increases IP3 production and subesequent Ca and activation of myosin - contraction
What role does PKA have in regulation of vasoconstriction
PKA can be activated by cAMP and leads to the activation of myosin phosphatasem inactivating myosin and relaxing smooth muscle
How do endothelial derived endothelins regulate vasoconstriction
A stimulus (hypoxia, thrombin, Glucose) leads to the transcription of big endothelin. Big endothelin is converted to ET-1 by ECE (endothelin converting enzyme). ET-1 binds either ETA or ETB receptors. Both of these receptors activate PLC and lead to IP3 production, then calcium release which binds calmodulin and activates MLCK. This phosphorylates myosin and leads to its activation and subsequent contraction of smooth muscle.
What is the feedback mechanism in place in endothelial derived endothelins
Endothelial cells express the ETB receptor. The ET-1 produced from big endothelin acts on the endothelial cells themselves. This increases intracellular Ca in the endothelia which stimulates the production of NO via eNOS. NO has two effects.
- Inhibition of ECE
- NO diffuses into vascular smooth muscle cells to induce relaxation.
How does angiotensin II activity regulate vasoconstriction
Angiotensin I is converted to angiotensin II by ACE on endothelial cells. Angiotensin II binds AT1 on vascular smooth muscle cells. This has a long term and a short term effect.
Long term: Activation of MAPK - Long term VSM gene expression that makes it more contractile
Short term: PLC activation, IP3, Ca, Myosin activity
