Building solutions for cardiovascular disease in women.

Although cardiovascular disease (CVD) is the leading cause of death both in men and in women, its effect is still largely underestimated in women. The fact that clinical manifestations of ischemic heart disease in women are different from those commonly observed in men might partially account for this problem. However, newly increased awareness of sex-specific risks related to CVD has begun to contribute to recent declines in women's mortality rates: the National Center for Health Statistics (of the Centers for Disease Control) has reported a 10% annual reduction in women's deaths since 2000.1 The need to understand CVD sex differences has motivated both clinicians (to explore new therapeutic strategies) and basic scientists (to discover underlying sex differences in the mechanisms of disease progression and cardiac repair). Recently, we have come to understand that a “failure” in the capacity for endogenous repair of injured or aging myocardium contributes to the progression of CVD. This in turn has led to the notion that CVD might be, in part, a failure of stem-cell mediation of ongoing cardiac repair. Furthermore, the idea has arisen that replacing lost or damaged stem cells can prevent the progression of CVD or promote cardiac repair. Just as cell-based therapy provides new hope for repair after damage or disease, we posit that a better understanding of sex and functional differences in cardiac stem-cell types could lead us to develop sex-specific strategies that afford a major advance in the treatment of cardiovascular diseases. Our group has begun to profile sex differences in progenitor cells in the blood of men and women. As shown in Figure 1A, the percentage of circulating progenitor cells decreased with age more rapidly in men than women. We also have found important sex differences in the repair of atherosclerosis,2 which involves differences in both the stem cells present and the cytokines produced in male and female apolipoprotein-E knockout (apoE–/–) mice—a model of atherosclerosis that mimics human disease. For example, the incidence of coronary artery disease differs in males and females—beginning sooner in males, with “catch-up” occurring in females by the 8th decade (Fig. 1B). 2 We have also observed that the loss of stem cells occurs with aging and differs by sex—dropping faster in men than in women (Fig. 1A). In our animal model,3 we were able to show that loss of a particular bone-marrow-derived angiogenic stem-cell population (Fig. 1C), CD34+ cells, decreases with age differently in males and females in a manner that inversely correlates with the progression of atherosclerotic disease (Fig. 1D). 4,5 Further, our studies have shown that bone-marrow-derived mononuclear cells from male and female apoE–/– mice present distinct atheroprotective capabilities.3,6 The administration of bone-marrow mononuclear cells (BM-MNCs) derived from female donors attenuated plaque formation in male atherosclerotic apoE–/– mice. This result was associated with a significant increase in the frequency of AC133+/CD34+ cells in the bone marrow of recipient mice. Endothelial progenitor cells highly express AC133+/CD34+ and have an important role in re-endothelialization and vascular repair.7,8 Moreover, previous studies have shown that the frequency of bone-marrow-derived cells in lesion-prone areas of apoE–/– mice is markedly increased.9 However, we posit that cell therapy is not a regenerative strategy simply because cells can integrate into injury sites and participate in new tissue formation, but also because these cells can shift the recipient's balance away from an inflammatory injury state, toward a condition that is more anti-inflammatory and reparative.10 In fact, we observed that the delivery of reparative female BM-MNCs induced an increase in bone-marrow CD45+ cells and plasma levels of granulocyte colony-stimulating factor in recipient male apoE–/– mice, which suggests that monocytes might also be involved in this reparative process.3 Monocytes are key effectors of immune homeostasis and play a crucial role in vascular injury repair.11 Fig. 1 A decrease in bone-marrow vascular progenitor cells is a proposed underlying mechanism in the progression of cardiovascular diseases in men and women. A) Our data indicate that stem cells decline throughout life and that this drop appears to occur . Patients with high cardiovascular risk factors show a significant increase in inflammation and an impairment in the ability of their cells to undergo chemotactic migration toward growth factors such as vascular endothelial growth factor (VEGF),12,13 which suggests that abnormalities in monocyte function could be one of the factors responsible for reduced vessel growth and for vascular complications in patients with cardiovascular risk factors. In addition, the number of the colony forming unit-Hill, composed of monocytes and macrophages, has been reported to correlate with risk factors and is considered a potent biomarker of vascular health in men.14 Sex differences were further explored by Hoetzer and colleagues,15 who showed that the colony-forming capacity and migratory activity of endothelial progenitor cells (EPC) are significantly higher in middle-aged women than in middle-aged men, which might confer a protective advantage upon women. Although there were no differences between men and women in Framingham risk score, the estimated 10-year coronary heart disease risk was significantly higher in men in the Framingham study. However, no correlation was found between risk score or estimated risk and EPC colony number or migration. The small population size (25 men and 25 women) might account for the differences between this and previous studies.14 Studies have shown that hearts from age-matched adult women are protected against ischemia-reperfusion injury, possibly due to decreased myocardial tumor necrosis factor-alpha (TNF-α), interleukin-1 (IL-1), and IL-6 (mRNA, protein), and possibly also to decreased activation of the p38 mitogen-activated protein kinase pathway. When exposed to ischemia, mesenchymal stem cells (MSCs) from female mice exhibit decreased apoptosis, as well as decreased TNF, decreased IL-6, and increased VEGF expression, in comparison with male MSCs,16 which confirms a sex-selective advantage to myocardial injury among female MSCs. In corroboration with these studies, MSCs derived from female rats induce greater protection after ischemia-reperfusion injury than do male MSCs.16 We have gathered early data showing that preclinical observations in mice—to wit, a loss of stem cells occurs with aging and differs by sex—is also observed in human beings. As we begin to observe that the presence of specific stem cells is associated with positive responses in clinical studies17 (for example, the association of CD133 and CD34+ cells with autologous stem cells in patients treated for heart failure), the need to understand changes in stem-cell number and function increases. Future work must explore the mechanisms involved in stem-cell sex differences. Sex differences as they affect progenitor cell phenotype and function have been overlooked in many clinical and experimental studies. A better understanding of these differences, and of the mechanisms involved in disease progress and repair, might yield a major advance in the treatment of cardiovascular diseases.