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Growth factors in preeclampsia: A vascular disease model. A failed vasodilation and angiogenic challenge from pregnancy onwards?

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Abstract

Preeclampsia is the major cause of maternofetal and neonatal morbi-mortality including intrauterine growth retardation, miscarriages and stillbirths. Inadequate vascular dilation and angiogenesis represent the crucial underlying defect of gravidic hypertension, denoting a failed response to the vasodilatory and pro-angiogenic challenge imposed by pregnancy, especially if multifetal. A similar pathogenesis appears involved in gestational diabetes. In this review we aimed to provide a hint on understanding the deeply involved angiogenic disorders which eventually culminate in utero-placental failure. The key players in these complex processes may be found in an intricate network of growth factors (GFs) and GF inhibitors, controlled by several vascular risk factors modulated by environment and genes, which eventually impact on early and late cardiovascular outcomes of mother and fetus.

Introduction

Hypertension is the most frequently observed disease in pregnancy. Pre-existing forms complicate more than 3% of pregnancies and new-onset types occur in about 7% of nulliparous pregnant women, with up to 15% of affected pregnancies and more than 25% of antenatal admissions [1]. In the United States preeclampsia (PE) account for 15% of all maternal deaths [2], and it represents the second largest cause of maternal mortality worldwide [3]. High risk of PE is reported in women with obesity, diabetes, latent renal dysfunction or undergoing twin pregnancies [4]. New-onset hypertension, with or without proteinuria, develops in 6–7% of pregnancies [1], and is complicated by PE in about 15–45% of cases [5]. Chronic hypertension is conversely reported in about 1–5% of pregnancies [1] and, when not associated with later superimposed PE in 25% of cases [6], it exhibits a relatively benign course [7].

The prototypical pregnancy hemodynamic change is a decrease in mean arterial pressure (MAP), with a nadir between the 16th and 20th week, obtained by an increased maternal and fetal vascular capacitance. This variation is caused by a powerful vasodilator and pro-angiogenic stimulus exerted by high vascular endothelial growth factor (VEGF) levels induced by estradiol (increasing up to 80-fold [8]) and by progesterone [9]. In the first trimester blood pressure (BP) is reduced by about 8–10 mmHg (Fig. 1A), but, even during the luteal phase of the menstrual cycle, a similar fall in BP takes places [10], which is maintained during conception. In this condition a further increase in VEGF levels [11], critically activated by insulin-like growth factor-1 (IGF-1), sustains endometrial angiogenesis [12]. Indeed, from ovulation onwards, IGF-1 and a protease enhancing its tissue availability [13], pregnancy-associated plasma protein-A (PAPP-A), are proved to be crucial players in a correct physiology of fertilization and early pregnancy [14]. Moreover a positive feedback of IGF-1 and IGF-1-promoted estradiol [15] on progesterone synthesis, is described in both conditions [16]. In particular, the estradiol to progesterone ratio, coordinates the decrease in uterine vascular impedance according to ovarian cycle and pregnancy [17]. Conversely, VEGF axis inhibition has been shown to prevent pregnancy in experimental [18] and human settings [19]. By improving maternal BP regulation, trophoblast invasion and utero-placental flow, VEGF, IGF-1 and other vasoactive factors including NO donors, have been described to influence both systemic and local vasodilating adaptations to pregnancy [20]. Many growth factors (GFs) have been proved to be involved [21] (Fig. 1B).

During gestation, after the 20th week, the BP gradually increases, returning to the pre-gestational level at about the 40th week [4]. Simultaneous variations in cardiac output (CO), mainly due to increased renin angiotensin aldosterone system (RAS) activation, do occur [22]. In particular, the peak CO is reached between the 16th and the 20th week, reaching 40% greater values than baseline, both through increased stroke volume (SV) and heart rate [23] (Fig. 1A). A substantial increase in prostaglandins partly counteract this RAS burst [17], and GFs such as IGF-1 and VEGF impact on both vasodilation and vascular bed extent [24], by inducing angiogenesis and increasing myocardial performance [25], even under stress condition [26]. The increased CO is associated with higher circulating blood volume (BV) with possibly ensuing left ventricular eccentric hypertrophy [27] (Fig. 1A and B).

Although the understanding of physiological variations during pregnancy is well established and PE is a long known and studied condition, a deep comprehension of mechanisms of pathogenesis and prevention of hypertension in pregnant women is still lacking. Recent data point to the possible causal role of impaired vasodilating GF physiology on PE development, as well as on their rescue potential [28], which ultimately highlight the protective role of nitric oxide (NO) against both PE and hypertension [29].

Section snippets

A hemodynamic perspective

The etiology and pathophysiology of hypertensive disorders in pregnancy still remain largely unknown, despite extensive research. Explanatory theories consider maternal hypertension the consequence of a fetal-promoted reduced release of trophoblastic factors [3] or a fetal-induced response to the hypoperfusion caused by inadequate placentation [30]. Alternative interpretations have suggested direct placental-mediated delivery of toxic or apoptotic factors, proteins or placental fragments [3].

Evidence of genetic modulation

Although the majority of cases of PE are sporadic, genetic factors may play a role in the predisposition to develop PE. The differences in risk among ethnic groups and the doubled PE risk in patients with first-degree relatives who have suffered from PE, suggest a role for genetic factors in the pathogenesis of PE [101].

Genetic factors may also play an important role in setting the balance of angiogenic factors in patients with PE. Recently, allelic variations in several VEGF and sFlt-1

Late cardiovascular effects

It is estimated that women with severe and early PE during their first pregnancy have an increased risk of recurrent PE in subsequent pregnancies, even higher with earlier and more severe PE manifestations (25–65%) [108]. Moreover in the brief term women experiencing PE, GDM or PIH exhibit a higher disposition to hypertension, hyperglycemia [109], thrombotic disorders [110] and endothelial dysfunction [111]. Several, not always consistent data [112], report or investigate [113] also long-term

GFs in pregnancy course

As already mentioned, although clinically evident after the 20th week of gestation, PE is generally accepted as a disorder of embryo implantation due to a lack of complete cytothrophoblast invasion of the spiral arteries, inducing ischemia of the fetoplacental unit from the 12th week onwards. IGF axis, namely IGF-1 [127] and IGF-2 [128] with their receptors and binding proteins, has been indicated as the main determinant of an appropriate placentation, by allowing adequate proliferation,

Insights in therapy

Recently published interesting data seem to converge on the concept that both non-pharmacologic and drug management of PE and PIH share non conventional action mechanisms involving GF modulation (Fig. 8).

The primary issue addressed in a correct management of PE is the early identification of women at increased risk of complications, and candidate for antihypertensive therapy. In this regard the mainly screened and detected risk indicators, such as kidney disease, secondary hypertension,

Conclusions

Strong evidence, here reported, suggests that both hypertension and proteinuria and diabetes gestational syndromes may be regarded as the epiphenomenon of a failed response to the vasodilatory and pro-angiogenic challenge that pregnancy imposes to the mother, all the more if multifetal. If maternal potential fails to adequately provide increased angiogenic and vasodilator processes to the demanding maternofetal unit development and hemodynamics, with its own additive vascular bed(s) and BV, the

Conflict of interest to declare

None.

E. Conti, MD, PhD, is an assistant cardiologist in the Intensive Cardiac Care Unit at the Faculty of Medicine and Psychology, Department of Clinical and Molecular Medicine, Sapienza University, Rome, Italy. She graduated in medicine, and afterwards achieved a specialization in Cardiology in 1998. She then obtained a PhD in molecular and cellular cardiology from the Catholic University School of Medicine in Rome working on the subject of IGF-1 and myocardial infarction in 2003. While working in

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    E. Conti, MD, PhD, is an assistant cardiologist in the Intensive Cardiac Care Unit at the Faculty of Medicine and Psychology, Department of Clinical and Molecular Medicine, Sapienza University, Rome, Italy. She graduated in medicine, and afterwards achieved a specialization in Cardiology in 1998. She then obtained a PhD in molecular and cellular cardiology from the Catholic University School of Medicine in Rome working on the subject of IGF-1 and myocardial infarction in 2003. While working in the Cardiac Intensive Care Unit organization and teaching, Acute Cardiac Care in Cardiology Specialization she got the European Accreditation in Intensive Care Unit in 2008 and a master's degree in Clinical Competence in Cardiac Intensive Care from the Florence University School of Medicine in 2010. She does research into acute coronary syndromes and growth factors in vascular disease biology, and works and investigates in the field of diabetes and acute coronary syndromes in both young and elderly. Moreover, her research group has recently focused on exploring the role of growth factor deficiency in atherothrombosis also in cancer patients treated with targeted drugs, and in hypertensive disease.

    L. Zezza, MD, graduated in Medicine in 2011, is now an attendant physician at the Cardiology Ward, at the Faculty of Medicine and Psychology, Department of Clinical and Molecular Medicine, Sapienza School of Medicine, Rome, Italy. He does research into hypertension, acute coronary syndromes and growth factors in vascular disease biology at both the bench and bedside level. He leads functional vascular examinations. He assists in the practical teaching and in tutorials for medical students with particular focus on the semeiotics and clinical history collection of main cardiovascular diseases. He is going to complete his clinical cardiology curriculum, aiming to develop expertise in the field of acute coronary syndromes and intensive cardiac care in cardiology.

    E. Ralli, MD, graduated in Medicine and Surgery in 2011, and in 2012 she won a student grant in medicine. She has practiced Family, Emergency and Urgent Care Medicine and she is now an attendant physician at the Gynecology and Obstetrics Unit at Sant’ Andrea Hospital, Faculty of Medicine and Psychology, Department of Obstetrics, Gynecological and Urological Sciences, “Sapienza” University of Rome. She also attends Endometriosis Center at Sant’ Andrea Hospital since 2011, evaluating a large number of patients. She is going to complete her gynecological curriculum and at the present time she is working on various gynecological and obstetrical issues, with particular attention to clinical and research work on the subjects of infertility, contraception and thromboembolic diseases in pregnant women

    D. Caserta, MD, PhD, is Full Professor at the Faculty of Medicine and Dentistry at the University of Rome “Sapienza”, and Head of Unit of Reproductive Medicine at the St. Andrea Hospital, Faculty of Medicine and Psychology. After Specialization in Obstetrics and Gynecology in 1987 at Sapienza University, from 2000 to 2005 she worked at the University of L’Aquila as Associate Professor of Gynecology and Obstetrics, and there held the Chair of Gynecology and Obstetrics for the curriculum course in Pathophysiology of Human Reproduction and Endocrinology, working as Head of the Centre for Human Assisted Reproduction. Since 2006 Full Professor in Obstetrics and Gynecology, she is also Teacher and Head of Sterility –Fertility Unit at Sant’Andrea Hospital, Sapienza University and in the Midwifery Course, and holds the Chair of Sterility Course in Obstetrics and Gynecology Residency. Member of the Italian Board for foreign Medical Doctors, her main research topics are Human Reproduction and New Technologies in Obstetrics and Gynecology, and she is Member of the Scientific Committee of European Journal of Obstetrics and Gynecology and of Reproductive Biology, and member of several national sector societies. In 2003, she became Member of the Commission of the Ministry of the Environment for the study of Environmental Pollutants.

    M.B. Musumeci, MD, is a cardiologist at the Cardiology Unit, Department of Clinical and Molecular Medicine, Faculty of Medicine and Psychology at Sapienza University, Rome, Italy. She graduated in medicine in 2001, and achieved a specialization in Cardiology in 2005. Since 2006 she works at the Coronary Care Unit and at the Outpatient Clinic Unit for patients with cardiomyopathies, rare cardiac diseases, and for prevention of sudden cardiac death, at Sapienza University, Rome. She is Assistant Professor at Sapienza University since 2007, and teaches in the Curriculum course of Clinical Cardiology within training program in Cardiology, Faculty of Medicine, and Acute Cardiac Care training in Cardiology Specialization. She does research into cardiomyopathies and acute coronary syndromes and intensive care topics. Her main research interest is the study of sudden death and arrhythmic cardiomyopathies and in particular hypertrophic cardiomyopathy, by the use of several diagnostic techniques. Another topic of her clinical and research investigation is the genetic study of families bearing inherited cardiomyopathies. She cooperates in some multicentric worldwide studies on clinical characteristics and outcome predictors of these myocardial diseases.

    M. Moscarini, MD, is Full Professor of Gynecology and Obstetrics at Gynecology and Obstetrics Chair at Sapienza University of Rome. Since 2004 he is the Director and Chairman of the Department of Obstetrics, Gynecological and Urological Sciences, “Sapienza” University, Sant’Andrea Hospital, Rome, Italy. Formerly Head Professor of Gynecology and Obstetrics at the University of L’Aquila and Director of the Department of Gynecology and Obstetrics (1990 to 2001) and of the Specialization in Gynecology and Obstetrics, he was also Chairman of the University Training Certificate in Obstetrics at the same University. From 1992 to 1996 he was the Coordinator of the Doctorate Research Programme in Gynecology and Obstetrics based at L’Aquila. President of Training Certificate in Obstetrics and currently Director of Gynecology and Obstetrics, Sant’Andrea Hospital. Since 2006 he is the Coordinator of the Doctorate Research Programme in Gynecology and Obstetrics based at Rome. His main clinical and research interest is devoted to gynecogical oncology and urogynecological surgery.

    C. Autore, MD, is the Chief of Coronary Care Unit, Faculty of Medicine and Psychology at Sapienza University, Rome, Italy. He graduated in medicine in 1976, and afterwards achieved a specialization in Cardiology in 1979. He works as Assistant Professor, since 1987, firstly in Non Invasive Cardiac Laboratory, and thereafter in 1997 as Chief of Coronary Care Unit, at Sapienza University, and then Associate Professor since 2001.

    Since 1997 he teaches in the Curriculum course of Echocardiography and Clinical Cardiology within training program in Cardiology, Faculty of Medicine. He also leads Cardiovascular Pathophysiology and Echocardiography teachings, in both Respiratory Diseases and Cardiology Specializations.

    Since 2004 he is also Cohordinator of the outpatient clinic unit for patients with cardiomyopathies, rare cardiac diseases and for prevention of sudden cardiac death. Since 2009 he is Director of the post graduate Master in “Techniques in Echocardiography”, and teaches “Techniques in Echocardiography”, at the same University.

    He does research into cardiomyopathies, acute coronary syndromes and echocardiography topics. His main research interest is devoted to the study of sudden death, arrhythmic cardiomyopathies and hypertrophic cardiomyopathy, through electrocardiographic, echocardiographic, ergospirometric, and magnetic nuclear medicine imaging techniques. He is running many multicentric worldwide studies on clinical characteristics and outcome predictors of these myocardial diseases. Genetic study of families bearing inherited cardiomyopathies is also a theme of his daily clinical and research investigation.

    M. Volpe, MD, FAHA, FESC, is Full Professor in Cardiology Chair at Sapienza University and Chief of Department of Cardiology at the same University since 1998. Graduated in 1976, he achieved Cardiology Specialization degree in 1978 at Naples University “Federico II”. Assistant Professor since 1982 at Naples University, he participated as Research Fellow in 1984-1985, and as Assistant Professor in 1987-1988, to the activities of Cardiovascular and Hypertension Center, Cornell University Medical College, New York Hospital (USA). Associate and then Full Professor in 1995, he moved to Rome and is Full Professor in Cardiology since 1998 at Sapienza University. Since 2001 he runs Cardiology Chair and is chief of Cardiology Department, and since 2010 director of Cardiovascular and Thoracic Sciences Department at Sant’Andrea Hospital, Faculty of Medicine and Psychology, Sapienza University. Since 2012 Director of the post graduate Master in “Nurse Competence in Intensive Cardiac Care”, at the same University.

    Ad hoc reviewer for many scientific journals, since 2003 he is Editor in Chief of High Blood Pressure and Cardiovascular Prevention and since 2012 Editor of Clinical Science, and participates to the Editorial Board of several other journals. He also holds the position of Coordinator of Vascular Research, at Angio-Cardio-Neurology, IRCCS Neuromed (Italy) since 1995.

    Member of the Board of Director of the Faculty of Medicine and Psychology, and member or coordinator of many National and international Research Groups, he is currently and up to 2014 President of the Italian Society of Hypertension, Charter Member of American Society of hypertension, Member of European/International Society of Hypertension and of Nucleus Heart and Hypertension –and of Nucleus Population and Prevention of the European Society of Cardiology. The main fields of his research work include neurohormonal control of circulation and cardiovascular structural and functional abnormalities in hypertension as well as heart failure and hypertension. He also promotes collaborative investigation on the genetic fingerprinting of cardiomyopathies.

    He has led many research programs in the field of hypertension pathophysiology and cardiovascular prevention and participated in several large international clinical trials and in the Steering Committees of many of them. In the position of Chief of Cardiology at the University of Rome has coordinated the clinical and research activity of a number of clinician scientists. Between honors, he received the Italian National Institute of Research Fellowship for medical and biological research (79-82), and the Italian National Institute of Research (CNR) NATO Fellowship for biomedical research abroad (84), and the Sebetia International Price for Medicine and Surgery – Silver Medal President of Italian Republic (2007).

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