Aging of lymph vessels: new facts and current
hypotheses
Anatoliy Gashev
Dept. of Systems Biology & Translational Medicine,
Texas A & M Health Science Center College of Medicine,
Temple, TX, USA
Lymphatic Function(s)
Maintenance of
fluid
homeostasis
macromolecular
homeostasis
Lipid
uptake from
the gut
Immune
reactions
Lymphatic Transport of
water
macromolecules
lipids
immune cells
Passive
and
active
forces
influencing
lymph transport
in lymphangions
arterial and venous pulsations;
respiration;
skeletal muscles contractions
respiration;
central
venous
pressure
fluctuations;
skeletal
muscles
contractions
lymph
formation;
gastrointestinal
peristalsis;
skeletal
muscles
contractions
contractions of lymphangions
(intrinsic lymph pump)
Lymphatic contraction – main driving force for
lymph transport
Isolated
cervical
lymphatic vessel
TP = 3 cm H2O
Contraction
Frequency ~ 16/min
data used for Gashev et al., 2004
What is necessary for the lymph transport?
Lymphangion is a morphological/functional unit of lymphatic vessels,
which contains upstream valve and portion of lymphatic wall before
the downstream valve (Term introduced by H. Mislin in 1960-s).
Gashev, scheme from 1991
Intrinsic lymph pump – influence of
transmural pressure
R. Elias & M. Johnston, 1988
N. McHale & I. Roddie, 1976.
A. Gashev, 1989.
Heterogeneity of the stretch-induced modulation
of pumping in lymphatic vessels
Gashev et al., 2004
factor creating active pulsatile flow –
contractions of muscle cells in lymphangions
Wall shear stress is another critical factor of modulation
the pumping activity in lymphatic vessels
Active pulsatile lymph flow creates fluctuations in
lymph velocity, wall shear stress and NO release
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H. Glenn Bohlen et al., 2009
B. Dixon et.al. 2006
Gasheva et al., 2006
arterial and venous pulsations;
respiration;
skeletal muscles contractions
factors creating extrinsic flow
lymph
formation;
gastrointestinal
peristalsis;
skeletal
muscles
contractions;
contractions
of upstream
lymphangions
Permanent non-pulsatile increases in wall shear stress inhibit
contractions of the lymphatic vessels
Influences of increases in axial pressure gradient on contractile
activity in isolated rat mesenteric lymphatic vessels in large
degree modulated by NO.
data used for Gashev et al., 2002
Regional heterogeneity in wall shear stress sensitivity in
lymphatic vessels
Gashev et al., 2004
How does aging influence lymph transport?
Aging-related alterations in stretch- and active
pulsatile flow-dependent regulation of contractility
in rat thoracic duct
Gashev et al., 2007
Aging-related alterations in imposed flow-dependent
regulation of contractility in rat thoracic duct – minute
pumping
adult
aged
data used for Gashev et al., 2002
Gashev et al., 2007
Contractility of the mesenteric lymphatic vessels
in 9 mo rats: in situ observations
T. Akl et al., AJP, 2011
Aging-related alterations of contractility of the mesenteric
vessels in 24 mo rats : in situ observations
T. Akl et al., AJP, 2011
Aging-associated alterations of contractility of the
rat mesenteric lymphatic vessels in situ
T. Akl et al., AJP, 2011
Aging-associated
alterations of contractility
of the
rat mesenteric lymphatic
vessels in situ
T. Akl et al., AJP, 2011
Comparison of contractility of
the rat mesenteric lymphatic
vessels in situ versus in
isolated preparations
T. Akl et al., AJP, 2011
Evidences of increased oxidative stress in aged
mesenteric lymphatic vessels
A. Aging-associated changes in SOD activity
B. Levels of lipid peroxidation
Thangaswamy et al., 2012, LRB
9 mo
Evidences of increased
oxidative stress in aged
mesenteric lymphatic
vessels
24 mo
A, B, C
In situ fluorescent labeling by superoxide
fluorescent indicator dye DHE
D, E, F
In situ fluorescent labeling by mitochondrial
ROS
fluorescent
indicator
dye
MitoTracker Red
Thangaswamy et al., 2012, LRB
Evidences of increased
oxidative stress in aged
mesenteric lymphatic
vessels
Western blot analysis of aging-associated
changes in SOD isoforms protein
expression and nitro-tyrosine formation in
rat mesenteric lymphatic vessels
Thangaswamy et al., 2012, LRB
Evidences of
increased
oxidative stress
in aged
mesenteric
lymphatic
vessels
Immunohistochemical
labeling (representative
images) and analysis of
aging-associated
changes in SOD protein
isoform expression and
nitro-tyrosine formation
in
rat
mesenteric
lymphatic vessels.
Thangaswamy et al., 2012, LRB
Acknowledgments
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David Zawieja Ph.D.
Michael Davis Ph.D.
James Moore Ph.D.
Mariappan Muthuchamy Ph.D.
H. Glenn Bohlen Ph.D.
Cynthia Meininger Ph.D.
Pierre-Yves von der Weid Ph.D.
Gerard Cote Ph.D.
Olga Gasheva M.D.
Tony Akl
Katherine Kelly
TAMHSC
University of Missouri
TAMU
TAMHSC
University of Indiana
TAMHSC
University of Calgary
TAMU
TAMHSC
TAMU
TAMHSC
Support: grants from NIH and Texas A&M University
[email protected]