Exercise and Endothelium

1
Exercise and Endothelium

• ???? ??????
• ???? ??? ???

2
Exercise and Endothelium

• ??? ??? ??? ?? ???? ????? ?????? ?????? ?????????
  ?? ???? ??? ????????? ? ?? ?????? ????? ??? ???
  ?????? ????? ??? ???? ?? ? ????? ???.

3
Endothelium

• ???? ??? ????? ????????? ?? ????? ?? ???? ????
  ???? ???? ???? ?? ??? ????? ???? ??? (????) ?? ??
  ?????? ? ??? ???? ?? ??? ????? ??? ? ?????????
  ?????? ???? ???.
• ????? ?? ????? ?? ????? ???? ?? ?????? ??????
  ?????????? ????? ? ?????? ????? ????? ?? ????? ??
  ???? ?? ??? ????? ??.
• ????????? ?? ??? ??????? ???? ?? ???? ???? ??
  ???? ??? ??? ???? ??? ??? ?? ????? ??? ?? ?????
  ????? ? ??? ???? ???? ? ???? ??? ????? ?? ?????
  ?? ?? ??? ????? ? ?????? ???? ????? ? ????? ???
  ???? ????????? ?????? ??????? ? ???? ???? ??? ???
  ?? ???? ?????? ? ????? ??????? ?? ????? ?? ?????.
• ??? ????? ?? 10136 ?? 1 ????????? ?? ??? ??????
  1 ??????? ????? ??? ?? ???? ???? 1 ?? 7 ??? ????
  ?? ?? ??????.

4
Endothelium
5
Endothelium Cell Function

• ?? ??? ????? ???? ????? ???????? ?????????? ?????
  ??? ????? ?? ???? ?????? ???? ?? ??? ???? ?? ???.
• Regulation of vascular tone.
• The induction of alteration in vascular
  structure.
• The interaction with blood cells.

6
Regulation of vascular tone

• ????????? ?? ??? ????? ?? ????? ????? ? ???? ???
  ????.
• ?? ??? ??? ??? ????? ????? ????? ?? ???? ??? ?
  ?????? ???? ??? ??????? ?? ???? ?? ????? ?? ?????
  ??? ?????? ? ???? ??? ???? ???.
• ????? ?????
• ????? ?????? ????? ??? ???? ????? ?? ???? ?? ????
  ?? ???? ??? ??????? ???? ?? ???.
• ?? ?????? ?? ?? ???? ?? ?????? ????? ? ?? ?????
  ?????? ????? ??? ?? ??? ???? ???? ??? ?? ????
  ??????? ??
• 1- ??? ?????? Pulsatile stretch
• 2- ????? ?? ???? ?? ??? ???? ?? ????? Shear stress

7
Regulation of vascular tone

• ?????? ?? ???? ????? shear stress ?? ???? ???????
  ??
• 1- Vasodilators such as Nitric axide (NO) and
  Prostacyclin (PGl2)
• 2-Vasoconstrictors such as endothelin (ET) and
  platelet factor (PAF).
• ???? ??? ??? ???? ??????? ???? ?????? ??? ????
  ????? ?? ???? ??? ????? ????? ?? ??? ?? ?? ????
  ????????? ???? ? ?? ???? ???? ?? ???? ?? ????.
• ???? ??? ????? NO ???? ???? ??? ???????? ????
  ?????? ?? ???? ??????? ???? ????? ? ????? ??????
  ????? ?? ???.
• ???? ???? (PGl2,ET and PAF) ??????? ?? ???? ??
  ??????? ???? ????? ???? ?? ????.

8
Regulation of vascular tone

• NO ????? ??? ?? ??? 1980?? ????? ???? ?? ?????
  ????????? ???? ?????. Endothelium-drived
  relaxing factor (EDRF)
• NO ?? ?????? ??? ?? ?????? ?? ???????? ???? NO
  ?????? ????? ?? ???. 3 ??? NO ?????? ???? ????
• 1- NOSI (nNOS) ?? ???? ????.
• 2- NOSII (iNOS) ?? ?????? ?? ???? ?? ???? ??
  ????.
• 3- NOSIII (eNOS) ?????? ?? ???? ??? ????????? ?
  ?????? ?? ????? ???? ? ????? ??.

9
Vasodilatory Agonists

• eNOS ?? ???? ??? ????????? ?? ??? ??? ???? ???.
• eNOS ?? ??????Ca2 ???? ????? ????? ?? ????.
  ????? ????? ???? ?? ???? (????? thrombin?
  bradykini adenosine 5-disphosphate? substance P)
  ?? ????????? ???? ?? ????? ???? ?????? Ca2 ????
  ????? ? ?? ????? ????? eNOS ???.
• NO ????? ?? ????? ?? ??? ?? ?? ??? ????? ??? ????
  ?? ???? ???? ???? soluble guanylate ? ????? cGMP
  ????? ?? ???.
• ?????? ???? ??? NO ???? ????? ????? ??? ???????
  ?????? ?? Ca2 ??? ?? ???? ?? ????????????????? ?
  ?? ??? ????? ??? ???? ?? ????.

10
Vasodilatory Agonists

• ???? ?????? ?? Ca2 ???? ??????Ca2 ???? ????? ?
  ???? ??? ???? ????? c ?? ????.
• ???? ????? ?? Ca2 ?? ??????sodium-hydrogen
  exchanger ? ???? ??? ??????? ????? c ? ???????
  ????? ??????? ???.
• ?????? ??? ???? ?? ??? ????? ??? ??????? ???? ???
  ????? ??? ?? ????
• ATP
• substances P
• Prostacyclin
• Endothelium-drived hyperpolarization factor (EDHF)

11
Vasodilatory Agonists

• ATP and Substance P which are release from
  endothelium cells by shear stress, stimulate
  specific receptors and cause the release of NO.
• A burst of Prostacyclin produced by endothelium
  cells could be observed after a sudden increase
  of shear stress.
• EDHF is a less well described product of
  endothelium cells. Stimulation with muscarine
  agonists leads to a release of EDHF causing a
  transient hyperpolarization of the cell membrane.

12
Vasoconstrictory Agonists

• ??????? ????? ?? ???? ?????? ???? ?? ???? ???????
  ??
• Endothelin-1 (ET-1) and Angiotensin II (AT2)
• ????? ?????? II ?????? ???? ??? ????????? ????
  ??? ??? ???? ???? Engiotensin converting enzyme
  (ACE) ? ?? ??? ????????? ????? ?? ???.

13
Vasoconstrictory Agonists

• ?? ??? ?????ET-1 ??? ?? ??????? ???????? ??????
  ??? ?? ?????? ???? ?? ???? ?? ?? ??? ???? ??
  preproendothelin-1 ?? ??? ??? ET-1 ???? ????? ??
  ???.
• ET-1 ?? ????? ?? ?????? ET-A ?? ?? ???? ?? ????
  ??? ????? ??? ???? ???? ????? ???? ??????
  ????Ca2 ???? ????? ? ?? ????? ?????? ??? ??
  ????? ??? ???? ?? ????.
• NO ????????? ?? ???? ???? ?? ????? ??? ???? Ca2
  ???? ????? ??? ???? ?? ??? ???? ?? ????.
• ??? ???????????shear stress ? ?? ??? ????? ????
  ?????? up-regulation ???? ET-1mRNA ??? ?? ??
  ????? ?? ????? ?? ???? ?? ?? ???? ??? ?????????
  ????? ?? Low shear stress ?????? ?? ???? ???? ??
  High shear stress ???? ?? ????.

14
Vasoconstrictory Agonists

• Angiotansin II ?????? renin-angiotensin? ?? ?????
  ????? ???? ??? ?? ???? ?? ?? NO ?? ?????????
  ????? ?????? ????.
• Angiotensin converting enzyme (ACE) ?? ??? ???
  ????????? ?? ???? ????? ????? ??????????? I ??
  ??????????? II ?? ??? ???? ???? ??? ???? ???
  bradykinin ? ???? ???? NO ?????? ?? ?? ?? ????.
• ????? ??? ????? ???? ?? ??????? ?? ???? ??? ?
  ???? ?????
• Endothelium-dependent regulation of vascluar tone
• ??? ????.

15
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16
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17
Endothelium-independent regulation of vascular
tone

• ??? ??????? ??? ??? ??? ??????? ?? ???.
• ??? ???? ?? ???? ??? ????? ???? ??? ???????
  ?????? ?? ??? ?? ??? ???? ???????? ?? ??? ??
  ????? ?? ???? ????? ?? ???? ???? ? ?????????????
  ?? ???.
• nonselective stretch-activation cation (SAC)
  channel
• ????????????? ?? ???? ??? ????? ?????? ?????? ??
  ????? ?? ???? ?? ??? ?? ???? ?? ???? ????? (?????
  ?? ???? ????? ?? SAC) ?? ???? ???? ?? ????.
• ???? ????? ?? ?? ?? ????? ???? ?? ?????? ????
  ???? ?? ????.
• ?? ?????? ???? ?????? ? ????????????? ????? ????
  ???? ??? ????? ??????? ?????? ?? ????? ? ????
  ?????? ?? ???? ? ?? ????? ???????????? ??? ????
  ?? ???.
• ??? ??? ?? ??????? ??????? ???? ???? ????? ?????
  ????????????? ? ?????? ???? ??? ???.

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Endothelium-independent regulation of vascular
tone

• Stretch
• Activation of cation channel in the plasma
  membrane
• Depolarization
• voltage-gated Ca2 channel
• 
  Ca2 influx
• Smooth
  muscle contraction

K channel Voltage-dependent K
outflux Hyperpolarization
19
Endothelium-independent regulation of vascular
tone

• Stretch
• Activation of cation channel in the plasma
  membrane
• Depolarization
• voltage-gated Ca2 channel
• 
  Ca2 influx
• Smooth
  muscle relaxation

K channel Voltage-dependent K
outflux Hyperpolarization
20
Vascular Control in Skeletal Muscle atRest and
During Exercise

• Endothelium-derived NO is a significant regulator
  of basal vascular tone in resting muscle.
• Its contribution to exercise-induced
  vasorelaxation in active skeletal muscle is less
  clear. No may be responsible for the initial (1
  min) hyperemic response mediating the dilatation
  of first- and second-order arteries, but not
  third- order arteries.
• Blockage of endothelium-derived NO did not alter
  the exercise-induced hyperemia in skeletal muscle
  of cat or rabbit.

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Vascular Control in Skeletal Muscle atRest and
During Exercise

• In human, interabrachial infusion of NO
  inhibitors produced a decrease of forearm blood
  flow at rest as well as during rhythmic and
  static exercise.
• Because of the same magnitude of reduction in
  blood flow at rest and during exercise, these
  finding suggest a lack of additional NO-mediated
  control of muscle perfusion during exercise.
• Whether other endothelium-derived vasodilators
  are involved remains to be investigated.

22
Flow-Induced Alterationsin Vascular Structure

• ?????? ?? ?? ????? ??? ???? ?? ??? ?????? ?????
  ???????? ?? ?????? ???? ?? ?????.
• ?? ??? ?????? ????? ?? ?? ??? ????? ??? ???? ??
  ??? ???? ?? ???? ?? ???? ????? ??? growth
  factor-beta ?? ?? ????.
• ?? ??? ???? ET-1 (????? ????? ????) ?? ???? ???
  ?????? ??? ?? ?? ????? ?????? ???? ?????? ?? ???
  ?? ????? ?? ???? ????? angiotensin II?
  platelet-derived growth factor-beta ? insulin
  ?????? ????.

23
Flow-Induced Alterationsin Vascular Structure

• ???? ?? ???? ?? ??????? ?????? ??? ????? ???
  ??????? ????? ??? ???? ???? ?? ?????. ???????
  ???????? ?? ??????? ???? ?????? ??? ????? ???????
  ? ?????? ?? ??? ?? ????? ?? ????? ?????? ???
  ????? ?? ?? ????.
• ?? ?????? ???? ?????? ??? ????? ??? ???? ????
  ???? ??????? ??????? ?? ?????? ???? ?? ???.

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Flow-Induced Alterationsin Vascular Structure

• Identified mediators involved in cell growth,
  extracellular matrix production, and proteolysis
  are
• 1- ET-1.
• 2- NO.
• 3-Plasminogen-drived growth factor (PDGF-beta).
• 4- prostacyclin.
• 5- Transforming growth factor-beta (TGF-beta).
• 6- Tissue plasminogen activator (t-PA).

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Flow-Induced Effect on Hemostasis/Thrombolysis/Fib
rinolysis

• NO ??? ?????? ??? ????? ????? ??? ???? ??
  ??????? ????.
• NO ????? ??? ???? NOSIII ?? ????? ??? ????????
  ???? ???? ????? ? ???? ??? ????? ?? ?? ???? ??
  ??? ? ????? ?? ?? ?? ????? ?? ?????.
• ???????? ?? ???? ??? ????? ?? ??? ?? ????? ??
  cGMP ?????? ???.

26
Flow-Induced Effect on Hemostasis/Thrombolysis/Fib
rinolysis

• ?? ???? ?? ??????????? ???? ???? ??? ??shear
  stress ?? ???? ??? ?? ???? ???? ?????
  ?????????? ????? ? ????? ??????? ?? ???? ?? ???
  ???.
• ?? ???? ?? ?????? ?????????? Ca2 ???? ????? t-PA
  ?? ???? ??? ????? ??? ????? ?? ?????? Ca2 ??
  ??? ?????? ????? ?? ????? ???? ?????? ????? ????
  ??? t-PA ???.
• NO? ??? ??????? ?? ?? ?? ?????? ???? ???? ??
  ?????. ??? ??? ?? ?? ?? ??????? ?? ???? ???
  ??????? ?? ? ?? ?? ????? ????? ??? ?????? ?????
  ?? ?????.

27
Effect of Physical Training onVascular Reactivity

• ?? ????? ?? ??? ??? ???? ?? ????? ???? ???? ?????
  ?????? ???? ?? ????? ?? ????? ????? ???? ???
  ?????? ??? ???.
• ????? ??????? ???? ???? ?? ???? ?? ?????? ?????
  ???? ??? ?? ????? ?? ??? ?? ??? ???? ? ???? ??
  ?????? ??? ???? ?????? ??? ?????? ?? ???.
• ????? ?? ????? ???? ?? ?????? ????? ???? ?????
  ?????? ?? ??? ??? ?? ?????? ?????? ??? ????? ???
  (???????? ?? ?? ??????? ????? ????? ?? ???) ????
  ????? ????? ??????? ?? ??? ????? ????? ???? ??
  ???.
• ??? ??????? ?? ????? ?? ????? ??? ????? ???? ??
  ?????? ??? ? ???? ??????? ???? ?? ????? ???????
  ?? ????.

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Receptor/Channel/Signaling Level

• The effect of training can be seen in
  enhancement
• In the expression of receptors
• In the contribution of channels
• On the signaling level.

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Transcriptional Level

• The training-induced long-term increase in blood
  flow modulates the expression of NO synthase.
• In cultured endothelium cells expose to long-term
  shear stress is NO synthesae up-regulated.

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Factors of Influence

• There are several factors that are important for
  the linkage between exercise and vascular
  adaptation.
• Magnitude and nature of flow.
• Vessel size.
• Frequency of exercise.
• Type of exercise.
• Time point of exercise training adaptation.

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The Effect of detraining

• In a study the plasma concentration of NO
  increased significantly while the plasma level of
  ET-1 decreased significantly at the end of
  eight-week aerobic exercise training (bicycle
  ergometer) and lasted through the fourth week
  after cessation of exercise training.
• These changes returned to the pre-exercise level
  after the eighth week.
• There was a negative correlation between plasma
  NO and ET-1 concentration.

32
Age

• Ageing is associated with a progressive decline
  in endothelium-dependent dilatation.
• In a study, using ultrasound technique, showed
  that the vasodilatator response, in male subject
  younger than 40 years was 70 higher than in
  older ones.
• Such differences were less pronounced when female
  subject were examined. However, another study
  demonstrated a progressive impairment in
  endothelium function in the ageing process for
  both genders. An explanation for the
  contradictory finding might be that the process
  occurs in men and women at different age.

33
Age

• Several study showed that aerobic exercise
  training can restore the age-related loss of
  endothelium-dependent vasorelaxation in old men
  and women even in previously sedentary ones.

34
Conclusion

• Finally, it is important to keep in mind that all
  the findings presented in this chapter have many
  limitation.
• Most conclusion drawn from these studies are
  based on either in vitro or animal models, with
  only a few derived from human studies.
• The others limitation are
• Broad variation in investigation techniques.
• Endothelium of different vessels, which differ in
  size and function.
• Different exercise type (intensity, duration).

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Conclusion

• Although data are conflicting, there is an
  overall trend toward an improvement of
  endothelium function caused by exercise.
• Beside on the presumption that endothelium
  dysfunction is systemic nature, one might assume
  that regular, especially aerobic, exercise
  produces favorable global endothelial
  adaptations.
• To complete the inchoate puzzle of existing data,
  further investigation is necessary.