New insights into the control of small artery function in human pregnancy and estrogen receptor beta knockout mice
Author: Luksha, Leanid
Date: 2007-04-27
Location: Hörsalen, NOVUM, plan 4, Karolinska Universitetssjukhuset, Huddinge
Time: 09.00
Department: Institutionen för klinisk vetenskap / Department of Clinical Sciences
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thesis.pdf (2.949Mb)
Abstract
Background: Available data clearly indicates functional and morphological
differences between small and large arteries, and observations from
studies on large arteries may not be applicable to understand the
physiology of small arteries (~200-300mum) that actively participate in
the regulation of peripheral vascular resistance, blood pressure and flow
to target organs. These events confer cardiovascular adaptation to normal
pregnancy (NP), however they are disturbed in preeclampsia (PE) and in
estrogen receptor beta knockout (ERbetaKO) mice at a certain age.
Aims: (1) To assess endothelial function and morphology with focus on the
role and mechanisms of endothelium-derived hyperpolarizing factor
(EDHF)-mediated relaxation in small subcutaneous arteries isolated from
pregnant women with and without PE; (2) To estimate the predisposition
for sex difference in blood pressure of ERbetaKO mice at the level of
small arteries function with a focus on endothelium-dependent dilatation
(EDHF) and adrenergic vasoconstriction.
Methodology: Small subcutaneous arteries obtained from pregnant women and
femoral arteries obtained from age-matched (14-22 weeks old) female and
male wild type (WT, ERbeta +/+) and ERbetaKO mice were used in a
wire-myography set-up for functional studies. Immunohistochemistry for
connexins (Cx) and/or ER subtypes (as appropriate), as well as scanning
and transmission electron microscopy techniques were also utilized for
evaluation of small arteries morphology with particular focus on
prerequisite for gap junction communications.
Results and conclusions: (1) The overall endothelium-dependent response
in arteries from pregnant women with and without PE was similar. However,
EDHF-mediated relaxation was reduced in PE. The results demonstrated
heterogeneity in the relative contribution of endothelium-derived factors
and in the mechanisms responsible for the EDHF-mediated relaxation in PE.
Gap junctions and/or H2O2 and/or cytochrome P450 epoxygenase metabolites
of arachidonic acid appeared to be involved in the EDHF-mediated response
in PE. In NP women, communication via gap junctions via Cx 43 represented
a common pathway responsible for EDHF action. The link between
morphological alterations within the vascular wall, and changes in the
contribution of gap junctions to EDHFmediated relaxation of small
arteries isolated from women with PE was suggested.
(2) Endothelium-dependent relaxation in arteries (<200mum of internal
diameter) was greater in WT females vs. males, and this was attributed to
a greater EDHF component in the relaxation. This difference was absent in
ERbetaKO mice. The data suggests that in WT male mice ERbeta reduces
EDHFmediated relaxation. The pharmacological evidence and morphological
prerequisite for involvement of gap junctions in EDHF-mediated responses
was indicated in male arteries. However, the absence of ERbeta had no
influence on expression of the main Cx subtypes within the vascular wall
or on the ultrastructure and morphology of the endothelium. The increased
EDHF contribution to endotheliumdependent dilatation in ERbetaKO male
mice vs. WT could not explain the hypertension observed in ERbetaKO
animals.
(3) Femoral arteries from ERbetaKO male mice demonstrated an enhancement
of the contractile response to alpha1-adrenoceptor agonist
(phenylephrine) that was accompanied by elevated basal tension
attributable to endothelial factors. Contractile responses to the mixed
adrenoceptor agonist, norepinephrine, were similar in ERbetaKO and WT
mice; however the addition of beta-adrenoceptor inhibitor unmasked the
enhancement of the underlying alpha1-adrenoceptor responsiveness
pertinent to males. beta-Adrenoceptor-mediated dilatation was also
enhanced in ERbetaKO vs. WT males. We suggest that ERbeta modifies the
adrenergic control of small artery tone in males, but not in females. The
alterations in the adrenergic modulation of small artery tone might
commence the hypertension in ERbetaKO males.
Significance: Heterogeneity in manifestation of functional and
morphological signs of endothelial dysfunction at the level of small
arteries in PE indicates a complexity and multifactor genesis of this
pregnancy-related disorder. The relative importance of ERbeta for the
control of small artery function found in males in the rodent model
substantiates a gender-related approach for prevention and treatment of
cardiovascular disease.
List of papers:
I. Luksha L, Nisell H, Kublickiene K (2004). "The mechanism of EDHF-mediated responses in subcutaneous small arteries from healthy pregnant women." Am J Physiol Regul Integr Comp Physiol 286(6): R1102-9
Pubmed
II. Lang NN, Luksha L, Newby DE, Kublickiene K (2007). "Connexin 43 mediates endothelium-derived hyperpolarizing factor-induced vasodilatation in subcutaneous resistance arteries from healthy pregnant women." Am J Physiol Heart Circ Physiol 292(2): H1026-32. Epub 2006 Nov 3
Pubmed
III. Luksha L, Nisell H, Luksha N, Kublickas M, Hultenby K, Kublickiene K (2007). "Endothelium-derived hyperpolarizing factor in preeclampsia: heterogeneous mechanisms and morphological prerequisites." J Physiol (Submitted)
IV. Luksha L, Poston L, Gustafsson JA, Hultenby K, Kublickiene K (2006). "The oestrogen receptor beta contributes to sex related differences in endothelial function of murine small arteries via EDHF." J Physiol 577(Pt 3): 945-55. Epub 2006 Oct 12 (Submitted)
Pubmed
V. Luksha L, Poston L, Gustafsson JA, Aghajanova L, Kublickiene K (2005). "Gender-specific alteration of adrenergic responses in small femoral arteries from estrogen receptor-beta knockout mice." Hypertension 46(5): 1163-8. Epub 2005 Oct 10
Pubmed
I. Luksha L, Nisell H, Kublickiene K (2004). "The mechanism of EDHF-mediated responses in subcutaneous small arteries from healthy pregnant women." Am J Physiol Regul Integr Comp Physiol 286(6): R1102-9
Pubmed
II. Lang NN, Luksha L, Newby DE, Kublickiene K (2007). "Connexin 43 mediates endothelium-derived hyperpolarizing factor-induced vasodilatation in subcutaneous resistance arteries from healthy pregnant women." Am J Physiol Heart Circ Physiol 292(2): H1026-32. Epub 2006 Nov 3
Pubmed
III. Luksha L, Nisell H, Luksha N, Kublickas M, Hultenby K, Kublickiene K (2007). "Endothelium-derived hyperpolarizing factor in preeclampsia: heterogeneous mechanisms and morphological prerequisites." J Physiol (Submitted)
IV. Luksha L, Poston L, Gustafsson JA, Hultenby K, Kublickiene K (2006). "The oestrogen receptor beta contributes to sex related differences in endothelial function of murine small arteries via EDHF." J Physiol 577(Pt 3): 945-55. Epub 2006 Oct 12 (Submitted)
Pubmed
V. Luksha L, Poston L, Gustafsson JA, Aghajanova L, Kublickiene K (2005). "Gender-specific alteration of adrenergic responses in small femoral arteries from estrogen receptor-beta knockout mice." Hypertension 46(5): 1163-8. Epub 2005 Oct 10
Pubmed
Issue date: 2007-04-06
Rights:
Publication year: 2007
ISBN: 978-91-7357-138-8
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