Endothelial Progenitor Cell Dysfunction in Polycystic Ovary Syndrome: Implications for The Genesis of Cardiovascular Diseases

PCOS-affected women have a number of reproductive and metabolic abnormalities. Previous studies of PCOS women with body mass index (BMI)-matched controls have proposed several CVD risk factors related to PCOS (17, 18). PCOS is frequently associated with obesity, elevated blood pressure, and dyslipidemia (19, 20); all of which are important risk factors for CVDs. PCOS patients have increased non-traditional risk factors for CVDs, such as elevated homocysteine (21-23), C-reactive protein (24), plasminogen activator inhibitor-1 (25), and fibrinogen (26) levels. In addition, our previous study has found evidence of a widening QRS complex (a biomarker for heart failure) on electrocardiogram in PCOS patients (27).

Through a calcium score analysis, PCOS patients had increased prevalence of coronary artery disease (CAD) independent of BMI and age. Shroff et al. have reported a correlation between CAD and PCOS using coronary artery calcium and inflammatory markers (28). Therefore, PCOS is an important risk factor for CAD. PCOS patients also have an increased risk of cerebrovascular diseases (29). Increased carotid intimal-medial thickness and carotid atherosclerotic plaque index scores have been reported in PCOS patients (30, 31). Asymmetrical dimethyl-L-arginine (ADMA) is an endogenous nitric oxide synthase (NOS) inhibitor, which can induce atherosclerosis and serve as an independent marker for cardiovascular morbidity (32). PCOS women have elevated ADMA (33), which may induce endothelial dysfunction in these patients. The above findings suggest that CVD risk, as reflected by endothelial dysfunction, is increased in PCOS patients. Table 1 summarizes the clinical evidence of PCOS in CVDs.

EPCs play critical roles in endothelial function and the genesis of atherosclerosis (34, 35). Bone marrow-derived peripheral EPCs can home to sites of vessel growth, where they proliferate and differentiate into mature endothelial cells for neovascularization (10). Aging, diabetes, hypercholesterolemia, and stroke are associated with impaired neovascularization, which may be caused by EPC dysfunction (36, 37). Peripheral EPCs isolated from CAD patients are significantly declined, revealing an impaired migratory response (38). Similarly, decreased EPCs may result in a poor outcomes after ischemic stroke (39).

Circulating EPC numbers and function were significantly reduced in diabetic patients with peripheral artery disease (PAD), and the severity of carotid stenosis was negatively correlated with the EPC number in these patients (40). In addition, angiotensin II and oxidative stress possibly contribute to reduced EPC number and function through activation of the AT1a receptor (41). Therefore, EPCs significantly contribute to the pathophysiology of CVDs.

Endothelial dysfunction is a common finding in PCOS patients (13, 42). EPCs have been shown to play a critical role in regulating endothelial function (43-45). According to recent studies, PCOS patients have reduced EPC numbers and impaired EPC function along with increased central arterial stiffness. Our studies have reported the presence of hyperinsulinemia and insulin resistance in PCOS patients (46, 47), which may result in EPC dysfunction through increased reactive oxygen species and impaired insulin signaling (48). When EPCs from insulin-resistant Zucker fatty rats were exposed to tumor necrosis factor-α, there was increased apoptosis and decreased AKT phosphorylation in the EPCs, which suggested that inflammation could induce EPC dysfunction. In addition, our studies found that hyperglycemia significantly modulated peroxisome proliferator-activated receptor and cardiac inflammation (49, 50), which were effects that have been shown to impair EPC function (51). Since PCOS is associated with a hyper-inflammatory status, inflammation-related EPC dysfunction could contribute to increased CVDs in PCOS patients. According to Gallagher et al. diabetic mice have an approximately 50% reduction in circulating EPCs compared to non-diabetic controls (52). PCOS is frequently combined with obesity, which can induce inflammation and oxidative stress, thus resulting in (42) EPC dysfunction. Oxidized lowdensity lipoprotein has been shown to impair EPC migration and endothelial NOS. Therefore, dyslipidemia from PCOS can also produce EPC dysfunction.

The prevalence of insufficient vitamin D is higher in PCOS patients (53). Vitamin D dysregulation and deficiency is correlated with CVDs and affects EPCs (54, 55). Therefore, administration of vitamin D may have beneficial effects on CVD risk factors in PCOS patients (56-58). Accordingly, vitamin D deficiency may reduce the EPC number and function in PCOS patients as a result of developing CVDs. Various environmental chemical toxicants have also been implicated in endocrine disruption that may be associated with PCOS. PCOS patients have a higher blood level of bisphenol A (BPA), an estrogenic endocrine-disrupting chemical used to produce plastics (59). Since chemical toxicants increase CVDs and are known to affect EPCs (60, 61), it is possible that chemical toxicants may reduce the EPC number and function in PCOS patients, thus increasing CVDs.