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Vascular Adaptations to Exercise
Presented by:
Cody Shaffer
May 5, 2005
Vascular Remodeling Outline
 Vascular Anatomy
 Arteriogenesis
 Angiogenesis
 Capillarization
Common Cardiovascular
Adaptations to Exercise
 Increased Heart Size (Hypertrophy)
 Increased Stroke Volume
 Increased Cardiac Output
 Increased Blood Flow
 Increased Vascular Density
Arterial Vascular Tree
 Conduit Arteries
(>1000 micro-meters)
 Resistance Arteries
(300-1000 micro-meters)
 Arterioles
(10-300 micro-meters)
 Capillaries
(<10 micro-meters)
Vascular Characteristics
Circulation Pathway
Vascular Function
 Arteries function to rapidly transport the blood
pumped from the heart.
-Expand in Diameter
 Capillaries function to exchange oxygen, fluid,
nutrients, electrolytes, hormones, and other
substances between the blood and interstitial fluid
in various tissues of the body.
-Increase in Numbers
Two Main Forms of Vascular
Remodeling:
 Arteriogenesis- Term applied to the
enlargement of existing arterial vessels.
 Angiogenesis- Formation of new capillaries
from existing capillaries.
Steps of Remodeling Flow Chart:
Arteriogenesis
 Occurs In Response To:




Elevated internal pressure within the vessel
Increased radial wall stress
Increased blood flow
Elevated stress on the endothelial surface
Arteriogenesis Cont.
 Vessel wall mass will increase to manage the increased radial wall stress
that occurs with high pressure or as the vessel diameter increases,
according to the Laplace relationship.
 Large increases in arterial blood pressure can also occur during intense
modes of exercise.
 Increases in flow velocity through a given arterial initiates extensive
enlargement of the artery.
 Increased flow velocity increases shear stress on vessel walls, which is
considered to be the primary stimulus that prompts vessel enlargement.
Factors Implicated in Arteriogenesis
 Arteriogensis depends on the presence of endothelium.
Shear stress up-regulates numerous factors implicated in
arteriogenesis.

These Factors Include:


Endothelial cell growth factors (VEGF) specifically VEGFR-2
Endothelial nitric oxide synthetase (eNOS)
Arteriogenic Factors
 Increased shear stress experienced by the endothelium translates to a
nitric oxide (NO)-dependent signal necessary for vessel enlargement
involving remodeling of the extra cellular matrix.
 NO is considered the most important mediator of flow-induced dilation.
 Through flow induced release of NO vasodilation can be enhanced
further and cellular growth response triggered either directly by
endothelial factors or indirectly by stretch and altered mechanical
stresses.
Arteriogenic Factors

Endothelial Cells react by activating endothelial NO synthetase
(eNOS) and genes for cytokines such as monocyte chemoattractant
protein-1 (MCP-1).

Aided by MCP-1 and adhesion molecules, circulating monocytes
adhere to invade the vascular wall.

Invasion of monocytes in the region of the collaterals contributes to the
vessel enlargement process via VEGF and fibroblast growth factor-2
(FGF-2).

After FGF-2 has bound to its receptors, endothelial and smooth muscle
cell proliferation is stimulated.
Process of Arteriogenesis:
Adaptations to Specific Training
 Huonker, M. et al. (1996)
Angiogenesis
 Occurs In Response To:




Elevated internal pressure within the capillary
Increased radial wall stress
Increased blood flow
Elevated stress on the endothelial surface
ANGIOGENESIS
Two Forms of Angiogenesis:
 Intusseception-
Refers to
the process by which a single
capillary splits into two
capillaries from within.
 Sprouting-
Refers to the
process by which activated
endothelial cells branch out from
an existing capillary to form a
cord-like structure.
Factors Implicated in Angiogenesis

There are many growth factors that are responsible
increased capillarity:

VEGF is a potent mitogen of endothelial cells that has
been implicated in the angiogenic response to exercise.

VEGF is required to maintain vascular integrity
because in its absence there can be a rarefraction of
vessels in the tissue.
Factors Implicated in Angiogenesis

VEGF acts in a proangiogenic manner that influences effectors of other
important steps in the vascular remodeling process, including the
following:

Cell signaling NO production.

Remodeling of the extra cellular matrix via up regulation of urokinaseand tissue-type plasminogen activator (uPA, tPA).

Up regulation of PA inhibitor (PAI-1) and uPA receptor (uPAR).

Up regulation of matrix metalloproteinase (MMP), which promotes
chemotaxis to assist productive migration of cells in tube formation.
Other Roles of VEGF in Angiogenesis
 VEGF is encoded by a single gene that is post-transcriptionally spliced
into several different isoforms.
 VEGF contains a signal sequence characteristic of protein designed for
export from the cell.
 VEGF is secreted by numerous tissue types, which establishes an extra
cellular matrix (ECM) of VEGF that is available for action upon
degradation of the ECM.
 The VEGF gene contains an upstream regulatory sequence that increases
VEGF and mRNA production when bound by hypoxia inducible factor
(HIF1).
Angiopoietins and Angiogenesis
 The angiopoitens (Ang1 and Ang 2) are recently discovered
cytokins that effect vascular remodeling.
 Ang1 promotes maturation and stabilization of vessels
through binding to and activation of the endothelial cellspecific tyrosine receptor (Tie-2).
 Ang2 augments angiogenesis by binding to but not
activating Tie-2.
Angiopoitens Cont.
 Ang2 to displaces Ang1 and destabilizes the
vasculature and makes it more responsive to VEGF.
 Ang1 and Ang2 are natural competitors to vascular
remodeling.
 Activity of Ang1 and Ang2 is dependent on the
presence of VEGF and there interaction is critical in
the angiogenic process.
Growth Factors Involved in Angiogenesis
 Fibroblast growth factors (FGF) are a family of angiogenic growth
factors that are mitogenic to all three of the cell types that comprise the
vasculature.
 FGF can aide in angiogeneis by up regulating VEGF and NO
production.
 FGF may also contribute to the continuation of angiogenesis as it is
released from the storage sites upon the degradation of the EMC.
 Activated endothelial cells can produce transforming growth factor-B
(TGFb), which recruits pericytes to help complete the newly formed
capillary.
OVERVIEW OF
Capillarization
 The exercised induced adaptations that occur within the
vascular tree increase the capillarity in tissues, organs, and
specifically skeletal muscle.
 Any increase in muscle capillarity is important in enhancing
blood-tissue exchange properties.
Effects of Capillarization
 A Greater Capillary Network:

Increases surface are for diffusion.

Shortens the average diffusion path-length within the
muscle.

Increases the time for diffusion exchange between the
blood and tissue.
Capillarization
 Refers to the increased capillarity within skeletal
tissue.
 Recent studies show that there is an even
distribution of capillarity within all fiber types
regardless of the mode of exercise.
 Capillarization is determined by the number of
capillaries in contact with each type of individual
fiber (capillary-to-fiber ratio).
Capillarization
Jensen et al. (2004)
Capillarization
 A study conducted by Jensen et al., looked at
the effect of intense training endothelial
proliferation, capillary growth, and
distribution of VEGF and FGFb.
 Two intermittent knee extensor training
protocols were conducted at 90% and 150%
of leg VO2max.
Capillarization
 Muscle biopsies were obtained throughout the
training periods for immunohistochemical
assessment of capillarization, cell proliferation,
VEGF, and FGFb.
 At 150% VO2max, micro dialysis samples were
collected from the trained and untrained leg at rest
and during exercise and added to endothelial cells
to measure the proliferative effect.
Capillarization
 After 4 weeks of training there was a higher capillary-to-fiber ratio and
increased number of endothelial cell associated proliferating cells than
before training.
 Neither the location of proliferative endothelial cells nor capillarization was
related to fiber type. The endothelial cell proliferative effect on of the
muscle microdialysate increased from rest to exercise in both the trained
and untrained leg.
 VEGF and FGFb were localized in endothelial and skeletal muscle cells and
training induced no changes in distribution.
 The results demonstrate that intense intermittent exercise induces capillary
growth and a transient proliferation of endothelial cells within 4 weeks, with
a similar growth occurring around both fibers.
Capillarization
Jensen et al. (2004)
Changes in capillary-to-fiber ratio in (A), capillarity density (mm2) in (B), and
proliferating cells (C) during the entire training protocol.
Summary
 Exercise imparts a powerful stimulus for vascular remodeling and
increased capillarity within working muscle, and an enlargement of
arterial vessels increasing flow capacity to the muscle.
 Vascular remodeling is a very intricate process that involves a
complex coordination among angiogenic growth factors, receptors,
and modulating influences including angiopoietins.

The vascular adaptations serve to enhance muscle performance by
increasing capillarization by increasing the muscles oxygen
exchange capacity and by increasing blood flow capacity.