Tommaso Simoncini

Inhibition of Vascular Smooth Muscle Cell Proliferation by Sodium Salicylate Mediated by Upregulation of p21Waf1 and p27Kip1

BackgroundSalicylates may have direct vascular effects by mechanisms that are independent of platelet inhibition. Methods and ResultsWe investigated the effect of salicylates on vascular smooth muscle cell (SMC) proliferation in response to platelet-derived growth factor (PDGF) in vitro. Salicylate concentrations of 5 and 10 mmol/L inhibited serum- or PDGF-induced SMC cell count and [3H]thymidine incorporation by 62% and 81%, respectively. There was no evidence of cellular toxicity or apoptosis as determined by trypan blue exclusion and FACS analyses. Because cell cycle progression is regulated by hyperphosphorylation of the retinoblastoma (Rb) protein, we examined the effects of salicylate on Rb hyperphosphorylation. Treatment with salicylate, but not indomethacin, inhibited nuclear factor-&kgr;B activation and completely abolished Rb hyperphosphorylation in PDGF-treated SMCs. This effect was associated with a decrease in cyclin-dependent kinase (Cdk)-2 and, to a lesser extent, Cdk-6, but not Cdk-4 activity, without changes in Cdk-2, -4, and -6 and cyclin D and E protein levels. Because Cdk-2 activity is regulated by the Cdk inhibitors p21Waf1 and p27Kip1, we studied the effects of salicylate on p21Waf1 and p27Kip1 expression. Treatment with salicylate prevented PDGF-induced downregulation of p21Waf1 and p27Kip1 but not of the Cdk-4/-6 inhibitor p16Ink4. ConclusionsThese findings indicate that high doses of salicylates inhibit SMC proliferation by cell cycle arrest at the G1-S phase and suggest a beneficial role for high-dose salicylates in the treatment of vascular proliferative disorders.

Molecular Basis of Cell Membrane Estrogen Receptor Interaction With Phosphatidylinositol 3-Kinase in Endothelial Cells

Objective—Nontranscriptional signaling mechanisms mediate some of the biological effects of estrogen, such as the rapid actions on the blood vessels. By interacting with phosphatidylinositol 3-kinase (PI3K), estrogen receptor (ER) &agr; leads to activation of protein kinase Akt and to subsequent increase in endothelial nitric oxide synthase activity. Because PI3K is mainly a cytoplasmic complex, we studied the cellular site of interaction between this enzyme and ER&agr;, and we dissected the molecular mechanisms that mediate this interaction. Methods and Results—By using cultured human saphenous vain endothelial cells, we found that cell membrane–bound ER&agr; colocalizes with PI3K and may be responsible for PI3K activation. Furthermore, we characterized the subsequent steps in the activation of the PI3K/Akt signaling cascade, comparing the molecular events that follow insulin or estradiol activation of PI3K. Conclusions—We provide novel evidence for an important role of nonnuclear estrogen receptor in rapid, nontranscriptional responses of human endothelial cells to estrogen.

Interference of Progestins With Endothelial Actions of Estrogens: A Matter of Glucocorticoid Action or Deprivation?

Estrogens play a pivotal role in sexual development and reproduction and are also implicated in a number of physiological processes in various tissues including the cardiovascular system. Epidemiological evidence suggests that endogenous estrogens protect women against coronary heart disease (CHD) before the age of menopause, and decreased CHD risk among postmenopausal women has been for a long time the main expected benefit of hormone therapy (HT).1 However, from the publication of the Women Health Initiative (WHI) results,2 medical practices of HT have been dramatically altered. Unexpectedly, large randomized controlled trials failed to demonstrate a beneficial effect of HT (conjugated equine estrogens combined [CEE] with medroxyprogesterone acetate [MPA]) for both secondary (Heart and Estrogen/Progestin Replacement Study [HERS])3 and primary CHD prevention (Women’s Health Initiative study [WHI]),2 and even revealed a detrimental effect during the year after the initiation of the HT. When women enrolled in the WHI study were divided according to the delay between onset of menopause and initiation of HT, the coronary risk tended to be lowered compared to placebo when HT is initiated during the first 10 years after menopause (hazard ratio for CHD=0.88).4 However, this risk tended to increase when HT was started 10 to 19 years postmenopause (hazard ratio for CHD=1.23), and the increase was significant when HT was started after more than 20 years (hazard ratio for CHD=1.66). See accompanying article on page 586 In striking contrast, and in line with epidemiological and cohort studies suggesting a protective effect of estradiol (E2), a large amount of data from experimental models of atherosclerosis (from mouse to monkey) demonstrated that endogenous as well as exogenous E2 …

Technological Breakthroughs in POP Surgery

The pelvic floor in women is a complex and highly vulnerable structure. Injuries and functional modifications of this complex due to pregnancy, life events, and aging often lead to pelvic organ prolapse (POP). Following the definition of a joint report by the two leading urogynecological societies [1], POP is defined as “any descent of one or more of the anterior vaginal wall, posterior vaginal wall, the uterus (cervix) or the apex of the vagina (vaginal vault or cuff scar after hysterectomy).” The different types of prolapse include apical vaginal prolapse, i.e., uterus and vaginal vault (after hysterectomy when the vaginal vault prolapses); anterior vaginal wall prolapse, i.e., cystocele (bladder prolapse), urethrocele (urethra prolapse), and paravaginal defect (pelvic fascia defect); and posterior vaginal wall prolapse, i.e., enterocele (small bowel prolapse), rectocele (rectum prolapse), and perineal deficiency. Women may present prolapse of one or more of these anatomical structures. POP may be associated with other pelvic floor dysfunctions such as sexual dysfunction, urinary incontinence (UI), chronic obstructive defecation syndrome (ODS), and constipation. Typical symptoms of POP are vaginal bulging, pelvic pressure, vaginal bleeding, discharge and infection, and low backache. All these symptoms have a profound social, psychological, and sexual impact, and they severely affect quality of life [2].

Menopause and Ageing

The decline in the reproductive capacity of women in the late fourth to fifth decade of life is accompanied by diverse sequelae, including vasomotor symptoms, an increased risk of osteoporosis, psychogenic disturbance and cardiovascular and cerebrovascular disease. Attempts to ameliorate losses in oestrogen through hormone replacement therapy (HRT) have, however, courted significant controversy relating both to increased risks of malignancy and vascular events, thereby standing as an exemplar for the difficulty in managing hormone balance during ageing. Dehydroepiandrosterone (DHEA) represents the most abundant sex steroid in plasma in men and women, but its serum concentration goes down to 10–20% of its maximum level by around the age of 70 years. Evidence suggest that lower levels of are associated with cardiovascular, cognitive and sexual impairment in women. Further aspects need to be better investigated, before drawing definitive conclusions on DHEA replacement therapy.