Vascular Smooth Muscle Flashcards
Vascular smooth muscle is found in which vessels, and more importantly, NOT found in which?
Arteries, arterioles, veins, and some venules
NOT IN CAPILLARIES!!
What are pericytes? Where are they found?
Contractile cells that wrap around the endothelial cells of capillaries and venules throughout body
What specific part of which vessel contains the greatest relative abundance of vascular smooth muscle?
Terminal arterioles (which also have the least elastic tissue of the vessels containing it)
How are smooth muscle cells arranged around arterioles?
Cocentrically
True or false: Multiple neurotransmitters can be co-released from a nueronal varicosity
True (varicosity= swelling)
(High/Low) density of sympathetic adrenergic varicosities are in arterioles
High
Which vessels are devoid of sympathetic innervation?
Capillaries, postcapillary venules, and small venules
Are sympathetic adrenergic varicosities close to vascular smooth muscle?
Yes, they can be
Sympathetic varicosities release multiple neurotransmitters near smooth muscle. List the important 3.
- Norepinephrine
- ATP
- Neuropeptide Y
Net effect of Norepinephrine release
alpha1 adrenergic receptor –> PIP2 cascade –> increase [IP3] –> SR Ca release –> vasoconstriction
Net effect of ATP release
Purinergic receptor P2x –> ligand gated Ca channel –> Ca influx –> vasoconstriction
Net effect of Nueropeptide Y (NPY) release
NPY receptor Y1R –> inhibits adenyl cyclase and activates phospholipase C–> decreases basal PKA –> vasoconstriction
(indirectly allows for more contraction, because PKA isn’t around to phosphorylate and thus inhibit MLCK. MLCK is needed for contraction)
PKA dependent phosphorylation of MLCK (inhibits/activates) MLCK. How?
Phosphorylation inhibits MLCK–reduces MLCK’s affinity for Ca-calmodulin
What occurs wen MLCK is inhibited?
no contraction of vascular smooth muscle –> vasodilation
In which type of vessel can contraction of a single smooth muscle reduce vessel diameter?
Precapillary arteriole
What is the effect of contraction of a single smooth muscle cell on mesenteric artery’s diameter?
No effect. (mesenteric supplies intestines and pancreas–dont need to supply them/digest when running from mammoth!)
The sympathetic nervous system promotes (vasodilation/vasoconstriction) through ___-adrenoceptor mediated elevation of intracellular Ca.
alpha1
Note: The source of Ca may vary depending on arterial region
RyR
ryanodine receptor-mediates release of Ca from the SR, essential step in muscle contraction
Little/many smooth muscles are needed to surround a mesenteric artery
many
the alpha1-AR signaling pathway for the mesenteric artery involves Ca influx and release form which two sources?
RYR and the InsP3R
What can inhibit the Ca response in smooth muscles cells surrounding a mesenteric artery?
Activation of endothelial cells
What activates myosin light chain kinase (MLCK)?
Calcium
What inhibits MLCK?
cAMP, and phosphorylation
Does vasoconstriction and vasodilation of vascular smooth muscle require depolarization?
NO! It an occur with or without depolarization
There are multiple mechanisms for modulating intracellular Ca in vascular smooth muscle. List a few
- Neurotransmitter/hormone –> Gq –> PIP2 –> Ip3 –> Ca release from SR –> Ca/CaM complex
- Potential dependent Ca channel
- Receptor activated Ca channel by neurotransmitter or hormone
- Ca pump, Na/Ca exchanger
An agonist may promote vasoconstriction by multiple pathways. We are most familiar with the Gq pathway–what is another important one?
Rho and Rho-kinase. Rough idea of cascade:
Agonist –> G12/13 –> GEFs –> Rho-GTP –> Rho-kinase –> phosphorylation of MLC –> contraction
PKA promotes (vasoconstriction/vasodilation)
Vasodilation (phosphorylates MLCK, decreasing MLCK’s affinity for Ca-Calmodulin)
Two ways PKA promotes vasodilation
- phosphorylation of MLCK
2. activates ATP-dependent K channel, resulting in hyperpolarization
Subsarcolemmal calcium sparks–what is their function and mechanism? What can initiate them?
They relax smooth muscle by hyperpolarizing the cell by activating a nearby BK(Ca) channel.
Initiated by Arachadonic acid metabolite 11,12 EET.
Note: The sparks are just a little burst of Ca, oterhwise you’d have a contraction.
Production of NO by ____ promotes ______
endothelial cells, vasodilation
eNOS synthesizs NO from L-arginine. What neurotransmitters stimulate this cascade? (4)
Acetylcholine, serotonin, thrombin, bradykinin
NO release from endothelial cells causes the conversion of what in vascular smooth muscle cell
GTP —> cGMP
how does cGMP promote vasodilation?
activates PKG which promotes:
- PKG –> increased myosin phosphatase –> myosin light chain dephosphorylation –> Ca desensitization of actin-myosin interaction
- PKG –> increase BK(Ca) –> hyperpolarization –> decrease Ca influx
Contraction of vascular smooth muscle is (thick/thin) filament regulated. Why?
Thick filament. Requires phosphorylation of a regulatory light chain in myosin by Ca-Cam-MLCK.
Note: THICK filament = myosin. THIN filament = actin. Myosin though has a LIGHT chain.
The level of myosin light chain phosphorylation is a balance between which two rates?
Rate of phosphorylation by MLCK, and dephosphorylation by myosin phosphatase (MP)
Rho kinase pathway can inhibit ____, resulting in wat?
myosin phosphatase, resulting in increase of Ca sensitivity of smooth muscle contraction
Why is the coronary vasculature pretty resistance to alpha receptors?
Don’t want to cose down vasculature of the heart. more beta receptors as a result
3 factors allowing smoth muscle relaxation
K(ATP) channels, NO, Adenosine
Transmural pressure
the pressure difference between two sides of a wall
When transmural pressure increaes, signaling pathways promote muscle contraction. Why does this occur?
Allows arterioles to increase resistance in response to increased blood pressure, to maintain constant blood flow
pressure = flow x resistance
What is the purpose of the myogenic reflex?
Auto-regulatory mechanism to help maintain flow at a metabolic rate as perfusion pressure increases.
Myogenic reflex (does/does not) require the endothelium
does not.
As transmural pressure increases over time (cm H20), arteriolar diameter (increases/decreases)
Decreases (shallow slope)
Myogenic reflex involves the following 2 events:
- stretch activated channels
- intracellular signaling
In the myogenic reflex, what do stretch channels cause?
depolarization, which opens up voltage-gated Ca channels
membrane potential of vascular smooth muscle. What does this result in?
-40 to -60 mV. Results in basal influx of Ca, hence basal level of contraction
Stretch activated channels (2 types)
- cation channels (TRP, EnaC)
2. chloride channels
3 types of intracellular signaling and function
- IP3
- DAG/PKC
- RhoA/Rho Kinase
DAG and Rho inhibit MLCP
IP3 causes release of Ca from SR
In addition to inhibiting myosin phosphatase, Rho also activates this inhibitor of myosin phosphatase
CPI-17
Hyperemia is an excess of blood in the vessels. Why does this occur during a baroreceptor vascular reflex?
Baroreceptor reflex reacts to decreased pressure (in carotid sinus). A bilateral carotid artery occlusion will increase blood pressure but also will cause a decrease in blood flow.
When the occlusion is released, there is a dramatic increase in flow. The release of the occlusion causes hyperemia–an overshoot–more than you bargained for.
What is reactive hyperemia?
Increase in blood flow following brief ischemia e.g. arterial occlusion (restriction in blood supply)
Why does hyperemia occur? Via what mechanisms?
During period of occlusion, tissue hypoxia and vasodilator metabolites build up (i.e. adenosine) –> elevates [cAMP] –> dilate arterioles and decrease vascular resistance. cAMP also activates PKA which inhibits MLCK and causes hyperpolarization via K(ATP).
When occlusion is released, pressure is restored and flow becomes elevated, due to decrease vascular resistance. (pressure = flow x R)
When do endothelial cells release nitric oxide?
In response to shear stress
NO is synthesized in endothelial cells by a
Ca-dependent nitric oxide synthetase (L-arginine + O2 –> NO + citrulline)
When NO diffuses into smooth muscle cells, what does it activate?
Activates guanylate cyclase –> cGMP synthesis –> activates PKG
3 ways PKG reduces levels of myosin phosphorylation
- phosphorylates MLCK (inhibits it)
- promoting myosin dephosphorylation
- activating BK(Ca) = big K channel, causes hyperpolarization, decrease in Ca influx
Thromboxane (TP) promotes (vasodilation/vasoconstriction)
vasoconstriction. feeds into PLC and Rho cascades
PGI2 (IP) = prostacyclin = prostaglandin = eicosanoid. Function? Mechanism?
It inhibits platelet activation and is also an effective vasodilator. Promotes vasodilation by elevating cAMP in vascular smooth muscle –> inhibits MLCK and activates K(ATP)
Role of hormone: angiotensin II. What metabolite has same net function?
When decreased blood pressure, Angiotensin II will cause an increase in vasoconstriction and help elevate blood pressure.
Thromboxane A2 also promotes vasoconstriction
Main determinant of vascular tone
Myosin phosphorylation
Myosin phosphorylation can by influenced by these 5 mechanisms
- intracellular Ca –> activates MLCK
- inhibition of myosin phosphatase –> increased net myosin phosphorylation
- Alter membrane potential: depolarization –> vasoconstriction
- increase [cAMP] –> inhibition of MLCK, hyperpolarization (K(ATP)), activation of MP
- increase [cGMP] –> activation of MP, hyperpolarization (BKca)
three arachidonic acid metabolites and function
prostacyclin (PGI2) and 11,12-EET –> vasodilation secondary to hyperpolarization and/or inhibition of MLCK
thromboxane A2 –> vasoconstriction
