Abstract-The two known estrogen receptors, ER␣ and ER, mediate the effects of estrogen in all target tissues, including blood vessels. We have shown previously that estrogen inhibits vascular injury response to the same extent in female wild-type (WT), ER␣ knockout (ER␣KO CH ), and ER knockout (ERKO CH ) mice. We generated mice harboring disruptions of both ER␣ and ER genes (ER␣,KO CH ) by breeding and studied the effect of 17-estradiol ( Using wild-type (WT) and estrogen receptor knockout (KO) mice, we have previously studied the role of ER␣ and ER in mediating the vascular protective effects of estrogen in a mouse carotid artery injury model. 10,17,18 Previous studies used mice developed at the University of North Carolina, Chapel Hill, which harbor gene deletions of either ER␣ (ER␣KO CH ) 19 or ER (ERKO CH ). 20 These studies show that treatment of ovariectomized female mice with nanomolar concentrations of 17-estradiol (E2) inhibits the response to vascular injury to equivalent levels in wild-type, 17 ER␣KO CH , 10 and ERKO CH mice. 18,21 These findings suggest that ER␣ and ER are able to complement one another such that each receptor alone is sufficient to mediate the vascular protective effects of estrogen, or that the vascular protective effects of estrogen are mediated by an ER␣/ER-independent pathway. To distinguish between these two hypotheses, we undertook the present study examining the effect of estrogen on the response to vascular injury in ER␣,KO CH (double) estrogen receptor knockout mice. Materials and Methods AnimalsA total of over 820 animals were required to ultimately generate the ER␣,KO CH mice used in this study. These mice, which have been extensively studied, do not express ER proteins in any tissue. 19,20,[22][23][24] However, ER␣KO CH mice have been shown previously to express mRNA for 2 partial ER␣ transcripts, one of which retains the hormone-and DNA-binding domains of full-length ER␣, and can Original
Therapeutic neovascularization for cardiovascular ischemia is a promising avenue in spite of disappointing early clinical trial results. The concept of three different mechanisms of neovascularization has served to define potential therapeutic targets such as vascular remodeling and stem cell recruitment, but it is anticipated that this will lose significance as the pleiotropic nature of angiogenic cytokines becomes fully understood. With the rapidly growing body of data on growth factors and pro-angiogenic strategies, approaches will emerge that are more effective than the ones that have been tested clinically thus far. Combinations of growth factors, for instance to stabilize vessels, or growth factors combined with cell transplants deserve more attention but will make the design of preclinical and clinical studies increasingly complex. Recent developments suggest that when using the appropriate dose and treatment regimens, even single growth factor therapy can result in stable and functional vessels. Whether gene therapy or protein therapy will be optimal for this purpose depends mainly on technical developments in vector design and production and on progress in the engineering of slow release matrix formulations for proteins. With the increasing complexity of therapeutic strategies, it remains imperative that these approaches are rationally based on fundamental and preclinical data.
SUMMARY:The present study provides evidence that chronic intake of a high-fat diet induces a dramatic extravasation of immunoglobulins, indicating alterations in blood-brain barrier (BBB) functioning, in the brains of apolipoprotein E (apoE)-knockout mice, but not of C57Bl/6 control mice. Using sodium fluorescein as a marker for the permeability of the BBB, we found additional support for age-related disturbances of BBB function in apoE-knockout mice. Behavioral analysis of apoE-knockout mice compared with C57Bl/6 mice indicated that they were also less efficient in acquiring the spatial Morris water maze task. Furthermore, apoE-knockout mice are known to develop severe atherosclerosis, which is exacerbated with a high-fat diet. We therefore compared the apoE-knockout mice with the apoE3-Leiden transgenic mice, which are known to develop atherosclerosis. However, apoE3-Leiden mice that were kept on a high-fat, high-cholesterol diet and that developed atherosclerosis to an extent similar to the apoE-knockout mice, showed no signs of BBB disturbances. These results indicate for the first time that apoE plays an essential role in the maintenance of the integrity of the BBB during aging and that it protects the brain from neuropathology induced by a high-fat diet. We therefore hypothesize that the role of apoE in the maintenance of the integrity of the BBB may be the mechanism by which apoE affects the progression of neurodegeneration, as seen in Alzheimer's disease. (Lab Invest 2001, 81:953-960).A polipoprotein E (apoE) is synthesized in almost all cell types and throughout the body. Within the brain, astrocytes are the predominant source of apoE (Pitas et al, 1987). It is thought that apoE functions by mediating neuronal repair and/or remodeling during development and during regeneration after injury to the central nervous system by mediating the distribution of lipids, predominantly cholesterol and phospholipids (Nathan et al, 1994).Three common human isoforms of apoE exist: E2, E3, and E4. ApoE4 is now a well-established risk factor for the development of Alzheimer's disease (AD) (Corder et al, 1993;Saunders et al, 1993). ApoE4 has also been associated with other neurological diseases, including vascular dementia and a poor clinical outcome in patients after stroke and head injury (Nicoll et al, 1995;Slooter et al, 1997). The mechanism by which apoE4 affects the process of neurodegeneration, however, is largely unknown.Mice deficient in apoE display disturbances in learning and memory function as well as in long-term potentiation (Krugers et al, 1997;Krzywkowski et al, 1999;Oitzl et al, 1997;Veinbergs and Masliah, 1999). They display several neuropathologic alterations, including a loss of synapses with increasing age, cytoskeletal alterations (Masliah et al, 1995), and a reduced activity of choline acetyltransferase (Gordon et al, 1995). In addition, they show an impaired response to ischemic, traumatic, and excitotoxic lesions (Chen et al, 1997;Laskowitz et al, 1997). On the contrary, a few studies report neit...
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