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Cerebral small vessel diseases (CSVDs) are a group of pathological diseases, accounting for more than 25% of ischemic stroke and more than 40% of all dementias
.
Although genetic forms have been found, sporadic SVDs are the most common, and the incidence increases with age
Blood vessel
A recent article in the PNAS magazine explored the important role of phosphatidylinositol 4,5-bisphosphate (PIP 2 ) in the neurovascular coupling damage of CSVDs
.
.
2
The metabolic demand of skeletal muscle is met in part by the expansion of blood vessels within the organs.
This expansion reduces the resistance to blood flow, so the increased demand is met by blood flow in the tissues
.
In contrast, the volume of the skull is basically fixed to prevent the overall increase in blood volume in the brain
The volume of the skull is basically fixed to prevent the overall increase in blood volume in the brain
In brain SVDs, neurovascular coupling is destroyed, and the weakened state of functional congestion leads to vascular cognitive impairment and dementia.
Dabertrand et al.
The vasculature of the brain is a hierarchical organization
.
The pial arteries form a highly interconnected network on the surface of the cortex
An emerging model of functional brain congestion focuses on the capillaries
.
Although the density of the capillary network in different brain regions is different, the standard distance from a position of the neocortical parenchyma to the nearest capillary is very small, about 13 μm
The initial signal event of functional hyperemia
.
(A and B) Neuronal action potentials induce hyperpolarization pulses in capillary endothelial cells to open Kir2.
The initial signal event of functional hyperemia
2.
The investigation of the reasons for the reduction of PIP 2 levels initially focused on the process of reducing PIP 2
.
In particular, traditional cognition points to PLC-mediated hydrolysis of G qPCR signals downstream of PIP 2
.
However, the inhibition of PLC did not affect the passivation of Kir2.
1 current activity, thus excluding the degradation pathway
.
Subsequent studies explored the synthesis of PIP 2 by lipid kinases , a low ATP affinity enzyme that requires high ATP levels
.
It is worth noting that the ATP level in the brain capillaries of CADASIL SVD mice decreased
.
This indicates that the reduction of ATP synthesis in brain capillary endothelial cells is the ultimate cause of the decline in PIP2 levels.
PIP 2 causes a cascade reaction, impairs the activity of Kir2.
1 channels, and leads to the failure of neurovascular coupling in CADASIL SVD mice
.
PIP 2 causes a cascade reaction, impairs the activity of Kir2.
1 channels, and leads to the failure of neurovascular coupling in CADASIL SVD mice
.
The reduction of ATP synthesis in brain capillary endothelial cells is the ultimate cause of the decline in PIP2 levels.
PIP 2 leads to a cascade reaction, damages the activity of Kir2.
1 channels, and leads to the failure of neurovascular coupling in CADASIL SVD mice
.
2
In summary, Dabertrand et al.
showed that the molecular basis of the defective neurovascular coupling associated with CADASIL SVD is a capillary Kir2.
1 channel disease caused by PIP 2 depletion
.
These findings provide a conceptual proof of the therapeutic potential of PIP 2 replacement
.
More generally, they can spell out the complete molecular sequence of the brain's SVD
.
However, the problem still exists
.
1 channel disease caused by PIP 2 depletion
.
The molecular basis of the defective neurovascular coupling associated with CADASIL SVD is a capillary Kir2.
1 channel disease caused by PIP 2 depletion
.
2 2
Is the PIP 2 exhaustion-dependent microvascular impairment unique to the CADASIL SVD model, or does it cause other brain SVD?
Is PIP 2 exhaustion-dependent microvascular damage unique to the CADASIL SVD model, or does it cause other brain SVD? 2A recent report showed that PIP 2 treatment can restore the impaired functional hyperemia in the 5xFAD mouse model of Alzheimer's disease, providing interesting evidence for a wide range of PIP 2 centered brain microvascular dysfunction models
.
As a potential clinical problem, how does the exogenous supply of PIP 2 enter the cell? Flipase on the plasma membrane can import extracellular PIP 2 , but this process requires ATP, and the capillaries of CADASIL SVD mice are damaged
.
Ca 2+ -dependent promiscuous enzyme activity does not depend on ATP, and PIP 2 can also be transported to the leaves of the plasma membrane
.
Understanding this transport process may be the key to unlocking the potential of PIP 2 for complementary therapy
.
The neurovascular coupling mechanism based on K+/kir2.
1 seems to drive the initial response to increased nutrients in a certain area of the brain on a 1-s time scale
.
Other aspects of neurovascular coupling work on longer time scales
.
A recently discovered complementary mechanism is that Ca 2+ influx in capillary endothelial cells triggers signal transduction from capillaries to arterioles through the transient receptor potential immobilized protein 1 (TRPA1) channel
.
The vasodilation signal initiated by TRPA1 is essential for maintaining functional hyperemia during prolonged somatosensory stimulation.
It spreads through a biphasic mechanism involving slow intercellular Ca 2+ waves and kir2.
1 determined by Longden et al.
Dependent electrical conduction mechanism
.
.
The vasodilation signal initiated by TRPA1 is essential for maintaining functional hyperemia during long-term somatosensory stimulation.
Ca 2+ inflow in capillary endothelial cells triggers the capillary to the small via the transient receptor potential immobilized protein 1 (TRPA1) channel Arterial signaling
.
The vasodilation signal initiated by TRPA1 is essential for maintaining functional hyperemia during long-term somatosensory stimulation, 2+ 2+
Therefore, PIP 2 consumption will damage the brain's functional hyperemia as much as possible, and this hyperemia is coordinated by different molecular sensors on multiple time scales
.
Loss of PIP 2 may be a common feature of brain SVD
.
.
The PIP 2 deletion may be a common feature of brain SVD of the PIP 2 2 depletion may impair brain function hyperemia, congestion and this is coordinated by a sensor on different molecules of a plurality of time scale
.
Loss of PIP 2 may be a common feature of brain SVD 2
Original source
1.
Earley S, Kleinfeld D.
PIP 2 as the "coin of the realm" for neurovascular coupling.
Proc Natl Acad Sci USA .
2021;118(21):e2106308118.
doi:10.
1073/pnas.
2106308118
Earley S, Kleinfeld D.
PIP 2 as the "coin of the realm" for neurovascular coupling.
Proc Natl Acad Sci USA .
2021;118(21):e2106308118.
doi:10.
1073/pnas.
2106308118 1.
Earley S, Kleinfeld D.
PIP 2 Proc Natl Acad Sci USA
2.
Darbertrand Fabrice, Harraz Osama F, Koide Masayo et al.
PIP corrects cerebral blood flow deficits in small vessel disease by rescuing capillary Kir2.
1 activity.
[J] .
Proc Natl Acad Sci USA, 2021, 118: undefined.
Darbertrand Fabrice, Harraz Osama F, Koide Masayo et al.
PIP corrects cerebral blood flow deficits in small vessel disease by rescuing capillary Kir2.
1 activity.
[J] .
Proc Natl Acad Sci USA, 2021, 118: undefined.
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