Blood Flow Regulation The Effects of Peripheral Vascular Disease

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Blood Flow Regulation The Effects of Peripheral
Vascular Disease
Jefferson C. Frisbee, Ph.D. Center for
Interdisciplinary Research in Cardiovascular
Sciences Robert C. Byrd Health Sciences
Center West Virginia University School of Medicine
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Overview of Presentation

• Basic Principles of Blood Flow Regulation
• Introduction of the Metabolic Syndrome
• Consequences for Vasculature and Perfusion
• Attempts at Amelioration
• The Brick Wall or The Challenge
• Philosophy

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Small Arteries/Arterioles are a Major Site of
Resistance
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Control over Perfusion

• Intrinsic Control
• That which arises from within the vessels and
  vascular networks (e.g., shear, myogenic,
  conducted)
• Allows for matching of delivery to demand (e.g.
  active hyperemia)
• Autoregulation
• Manifested by factors/stimuli acting on vascular
  smooth muscle
• Extrinsic Control
• That which arises from sources outside the
  vessels or vascular networks (e.g., sympathetic,
  parenchymal, humoral)

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Myogenic Activation - Concept
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Myogenic Activation - Pathways
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Locally Produced Vasodilators/Vasoconstrictors

• Metabolites derived from parenchymal cells
• linked to cellular metabolism
• sensitive to balance between O2 delivery and O2
  demand

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Endothelium
Plays a central role in cardiovascular
homeostasis (1) physical permeability
barrier (2) site for metabolism of some
vasoactive substances (3) confers
anti-thrombogenic properties to the vessel
wall (4) releases paracrine and autocrine factors
that influence vascular tone vascular
permeability vascular growth and remodeling
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Flow-related shear stress
The effect of luminal flow on arteriolar diameter
is due to shear stress on the endothelium
Shear Stress the force acting on a surface in
a direction tangential To the endothelial surface
Shear rate the velocity gradient in a moving
fluid.
Endothelial shear stress shear rate x blood
viscosity
Endothelial cells
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Shear-induced release of vasoactive factors
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Gap Junction Channels Electrical Syncytium
Communication between and among VSM cells and
endothelial cells
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Apply vasoconstrictor
Conducted response
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• Gap-junction coupling among endothelial cells
• Gap junction proteins (connexins) are different
  from those in vascular smooth muscle
• May contribute to the longitudinal conduction of
  some vasomotor responses along the vascular
  network (simultaneous conduction through VSMC and
  EC)

• Gap-junction coupling between VSM and endothelial
  cells
• Myoendothelial gap junctions ultrastructural
  and electrophysiological evidence, but no
  evidence for the presence of connexins at
  endothelial-smooth muscle cell junctions.
• The functional significance of myoendothelial
  gap junctions is unclear

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The Metabolic Syndrome
A combined metabolic/cardiovascular disorder
reflecting the concomitant development of
multiple risk factors for negative cardiovascular
outcome. Obesity Hypertension Dyslipidemia
Type II DM/Insulin Resistance/Hyperglycemia Pro-t
hrombotic/Pro-inflammatory state
Significantly elevates the risk for development
of peripheral vascular disease

• Concentrated in the lower limbs (gt80 of cases)
• Localized in the microcirculation, not treatable
  by angioplasty
• Symptoms include
• Dynamic (spasm) and passive occlusion (lesions)
• Exertional limb pain and fatigue
• Chronic ischemia, pain at rest

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Todays Lucky Contestants

• Due to a dysfunctional leptin receptor gene,
  resulting in chronic hyperphagia, OZR rapidly
  develop insulin resistance/type II diabetes,
  dyslipidemia, moderate hypertension and obesity
  an excellent model of the metabolic syndrome.
• The lean Zucker rat (LZR) is identical throughout
  the genome with the consistent exception of the
  leptin receptor gene, and is thus an appropriate
  control animal for OZR.

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The Dogma of the Metabolic Syndrome
Progressive peripheral ischemia at rest and under
conditions of elevated metabolic demand The
result of an impaired dilator reactivity of the
peripheral resistance arterioles in response to
physiological stimuli.
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Impaired Arteriolar Responses to Some Dilator
Stimuli
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But certainly not all
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Effects of PEG-SOD on Arteriolar Reactivity
Increased vascular oxidative stress contributes
to an impaired skeletal muscle arteriolar
reactivity to select dilator stimuli in isolated
and in situ arterioles.
What does this mean for skeletal muscle perfusion?
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In situ Rat GPS Preparation
ODrobinak and Greene (1996)
Fatigue resistance and active hyperemia of in
situ skeletal muscle response to elevated
metabolic demand are impaired in OZR versus LZR.
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Effects of PEG-SOD Infusion (2,000 U/kg)
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Effects of PEG-SOD Infusion (2,000 U/kg)
Dogma fails us.
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• So, where does this leave us?
• Some indices of vessel dilator reactivity are
  reduced, some are normal. Those that are down
  can be restored with anti-oxidant treatment.
• However, even though impaired dilator reactivity
  is ameliorated, skeletal muscle perfusion is
  still down.

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Another kick at it

• Why didnt anti-oxidant therapy work?
• Acute reduction of vascular oxidant stress only
  (use chronic)
• Severe levels of metabolic demand (use
  incremental)
• LZR/OZR on Tempol (1 mM, 5-6 weeks)
• 3 minute bouts of 1, 3, or 5 Hz twitch
  contractions

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Chronic Tempol Improves Dilation to NO-dependent
Stimuli
Acetylcholine (10-6M)
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Tempol Improves Perfusion at Mid-High Metabolic
Demand Only
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• Chronic reductions in oxidant tone have no
  identified beneficial effect on muscle perfusion
  at rest or with mild elevations in metabolic
  demand, where vasodilation should be most
  sensitive to modulation.

• The benefit of improved oxidant tone occurs with
  higher metabolic demand, where dilator influences
  are more severe and vascular tone is minimized.

From a perfusion standpoint, what else becomes
increasingly consequential as metabolic demand
increases?
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Minimum Vascular Resistance
OZR have an increased resistance across a
maximally dilated microcirculation versus LZR
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Arteriolar Remodeling
Skeletal muscle arterioles of OZR are less
distensible versus LZR, contributing to an
increased resistance to perfusion via structural
narrowing of arterioles.
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Microvascular Rarefaction in Skeletal Muscle of
OZR
25 mmHg increase in MAP
Is this just hypertension-induced reduction in
MVD?
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Microvessel Rarefaction at 11 weeks in OZR
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Microvessel rarefaction precedes
hypertension. What if hypertension never
develops?
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Microvessel Rarefaction with Anti-Hypertensive
Therapy
But neither hydralazine nor captopril are solely
anti-HT agents
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What is the real predictor of microvessel
rarefaction?
Dogma fails us.
Hypertension, classically considered a strong
stimulus for MV rarefaction, is not a predictor
of reduced MVD in OZR. However, insulin
resistance does correlate well with SKM MVD.
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Vascular Nitric Oxide Bioavailability
Low
High
LZR Control
LZR L-NAME
Hydralazine
OZR TEMPOL
OZR TEMPOL OZR L-NAME
Vascular Oxidant Stress
Allows for not only the assessment of potentially
ameliorative effects of reduced oxidant stress,
but also a separation of oxidant stress from
nitric oxide bioavailability.
OZR Control
High
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Improved MVD with Chronic NO Bioavailability, not
ROS
Skeletal muscle microvessel rarefaction in OZR
develops in response to chronic reductions in NO
bioavailability. The scavenging actions of ROS
merely represent one route through which this
occurs.
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Experimental Protocol

• LZR and OZR _at_ 6-7 weeks of age Sedentary (cage
  restricted) or Exercised (10 weeks of treadmill
  exercise 1hr/d, 6d/wk, 22m/min)
• Assessments of
• vascular structure/function
• microvessel density
• active hyperemia and minimum vascular resistance
• markers of inflammation

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Exercise Training Increased Vascular NO
Bioavailability and Microvessel Density
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Active Hyperemia and Minimum Vascular Resistance
were Improved with Exercise Training
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Correlations between MVD, Angiogenic Cytokines,
NO Bioavailability
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What have we learned about rarefaction in OZR?

• Elevated minimum vascular resistance and blunts
  active hyperemia at moderate-high metabolic
  demand
• Develops independent of hypertension, more
  accurately predicted by insulin resistance
• Develops as a result of chronic reduction in
  vascular NO bioavailability, elevated oxidant
  stress is only a means to an end
• Chronic exercise training will blunt severity of
  rarefaction, effect correlated with improved NO
  bioavailability and blunted inflammation (e.g.
  MCP-1, IL-1b, TNF-a)

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Endothelial Dysfunction
Vascular NO Bioavailability
Arteriolar Mechanics
Adrenergic Tone
Oxidant Tone
Microvessel Density
Blood Viscosity
Inflammation