Harraz and Jensen 2021 Vascular Ca2+ Flashcards
What are examples of calcium stores in a cell?
ER and SR
Mitochondria is comparable too
What is the Vm of SMCs? What are the Vm that causes contraction and dilation, respectively?
Around -40mV
-30mV and-60mV
State the relationship between polarization and contraction/relaxation.
Hyperpolarization = dilation
Depolarization = contraction
What are the channels that underlies establishment of arterial tone?
Cav1.2 channel
Also Cav3 channels but it initiates CICR to activate K+ channels to hyperpolarize and counteract tone
How does pressure relate to arterial tone?
Higher pressure causes depolarization and contraction to establish arterial tone
Are there non voltage dependent calcium channels involved? How are they activated?
Yes, TRP channels are non selective cation channels
GPCRs can activate TRPC channels -> allow Ca2+ influx
How do TRP channels contribute to de and hyperpolarization?
Activation of TRPC or IP3s can increase intracell Ca2+ then activate TRPM which causes depolarization via cation influx (but not Ca2+)
TRPV channel activation can allow Ca2+ influx by shear stress, which can activate Ca2+ activated K+ channels to hyperpolarize the cell
- TRPV4, RyR, BKCa can form a complex
Describe which RyR variant and how it’s involved in the vasculature. How does it differ from IP3Rs? Is it different from cardiac and skeletal muscle?
RyR2 in vasculature is expressed on SRs.
Cav3 mediated CICR causes Ca2+ sparks which activated Ca2+ activated K+ channels (BKCa) -> hyperpolarize and vasodilation, whereas IP3Rs causes a Ca2+ increase for depolarization via Chloride or TRP channels-> vasoconstriction
This is different from cardiac and skeletal muscles where RyR causes contraction
Why do Cav1.2 and Cav3.2 differentially modulate tone?
Cav1.2 (L type) are more long lasting whereas Cav3.2 is more transient and activated at hyperpolarized state, so smaller in magnitude -> induce localized CICR to activate BKCa
Describe the mechanism of Ca2+ uptake into stores, against the gradient.
Ca2+ ATPase pumps use ATP to mediate uptake into stores and efflux to outside cell.
SERCA into SR/ER and PMCA for outside the cell.
What is the difference between the nature of Ca2+ and depolarization between SMC and EC?
SMC Ca2+ (typically) causes depolarization and contraction
EC Ca2+ counteracts contraction via eNOS or by Ca2+ activated K Channels like IK/SK to hyperpolarize
What does endothelial Ca2+ typically cause in downstream?
Activates eNOS and produces NO for vasodilation
Also activation of PKC and CAMK
How does EC Ca2+ influence SMC contractility? Mechanism?
Ca2+ influx through TRPV4 or release through IP3R in EC can cause BKCa or IK/SK induced hyperpolarization which propagates to SMCs via gap junctions-> Vasodilation
What are mechanisms driving EC Ca2+ increase? Is it voltage gated?
Many are not voltage gated because through TRP channels
For example TRPV4 or Piezo1 senses shear stress due to increased blood flow -> Ca2+ -> hyperpolarize -> dilation
Alternatively P2X (purinergic) and NCX influx
Can also have the usual IP3R pathway and subsequent SERCA uptake
How is VGCC altered in aging? Give answers for both L type and T type channels
Change in L type is dependent on which vascular bed it is. (eg. cerebral vessels has reduced L type in aging and thus reduced tone)
T type (Cav3.2) current is diminished in aging, which would deplete depolarization mechanisms to vasodilate
Renders vessels less dynamic
How are intracellular Ca2+ stores and handling affected in aging?
IP3R and RyR mediated Ca2+ release and SR refill are suppressed in cerebral arteries SMC due to reduced expression of the channels
Storage is enhanced in some vessels like mesenteric
How is TRPC6 involved in SMC contractility? How is it altered in hypertension and aging?
adrenoreceptor activates GqPCR cascade to produce DAG (same pathway as IP3 production too, so both are produced) which activates TRPC6 to allow Ca2+ and Na+ influx -> constrict via crossbridge or depolarization
Wall stress or 20-HETE can also act on TRPC6 to cause constriction
Increased TRPC6 in hypertension to protect BBB but that increase is lost in aged hypertension
How is BKCa involved in SMC contractility? How is it related to aging?
Negative feedback regulator of constriction
Sexually dimorphic effect of aging in the brain
Male = increase expression -> reduced contraction
Female = decreased expression -> exaggerated contraction
How is EC Ca2+ altered in aging?
Decreased spontaneous local Ca2+ transients -> diminished EC-SMC communication
Diminished response to ACh for EC dependent vasodilation possibly due to enhanced IK/SK channel activation (ie. leaky conduction) -> loses electrical signal transmission
How are Ca2+ and cellular senescence related?
Aberrant Ca2+ signaling can cause cellular senescence
eg. oxidative stress driven by Ca2+
eg. Ca2+ can also drive proinflammatory and senescence related genes
