**3. Angiogenetic growth factors in FGR**

Numerous factors are thought to play a role in normal vascular adaptation to implantation. The VEGFs are specific stimulators of vascular permeability, as well as vascular endothelial cell protease production and migration, all of which are critical components of the angiogenic process [Folkman et al., 1987] Vascular endothelial growth factor also stimulate angiogenesis in a variety of in vivo and in vitro models [Klagsbrun et al., 1991]. The increased expression of VEGF-A, b-FGF, and eNOS that we have found in IUGR placentas may promote increased endothelial cell proliferation and migration and pathological angiogenesis [Kinzler et al., 2008].

VEGF, placental growth factor (PlGF), angiopoietins (Ang-1 and Ang-2) are involved not only in the regulation of vascular development and in remodeling during placentation, but also act as growth factors for driving growth and differentiation processes such as invasion. It has been hypothesized that an impairment of trophoblast invasion and a failure of spiral artery remodeling could have a role in the development of PE and FGR [Wulff et al., 2003].

Vascular endothelial growth factor-A (VEGF-A) and placental growth factor (PlGF) are probably the best-studied factors. VEGF interacts with VEGFR-1 (Flt-1) and VEGFR-2 (KDR) to promote endothelial cell proliferation, cell migration, and vascular permeability. PlGF shares biochemical and functional features with VEGF and interacts with VEGFR-1 (Flt-1). PlGF and VEGF-A have synergistic effects regarding angiogenesis, but vessels induced by PlGF are more mature and stable than vessels induced byVEGF-A [Chung et al., 2004]. PlGF is abundantly expressed in the human placenta. Both VEGF-A and PlGF may be important paracrine regulators of decidual angiogenesis and autocrine mediators of trophoblast function [Sherer et al., 2001].

A second family of growth factors, the angiopoietins, is also known for their regulating capacities regarding angiogenesis. Angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) bind with equal affinity to their receptor TIE-2, but have different functions. Ang-1 maintains vessel integrity and plays a role in the later stages of vascular remodeling [Geva et al., 2000]. Ang-2 is a functional antagonist of Ang-1 and leads to loosening of cell–cell interactions and allows access to angiogenic inducers like VEGF. Coexpression of VEGF and Ang-2 induces angiogenesis, but Ang-2 results in vascular regression in the absence of angiogenic signals. Ang-1 and Ang-2 have both been detected in decidual and placental tissues [Asahara et al., 1998].

Various decidual cell types are capable of producing angiogenic factors. We recently showed the production of PlGF, KDR, Flt-1, Ang-2, and TIE-2 by endothelial cells and extravillous trophoblasts. Decidual stromal cells, glandular epithelium, and perivascular smooth muscle cells were found to produce all studied angiogenic factors [Plaisier et al., 2007]. Uterine natural killer cells are also abundantly present in first-trimester decidua and are known to produce PlGF, VEGF, Ang-1, and Ang-2.

#### **4. Conclusion**

184 From Preconception to Postpartum

It is obvious that the regulation of HIF expression and function is achieved through a number of factors, such as PO2, VHL and PHD-1, 2 and 3. Consequently, a measurement of expression only of HIF in conditions with decreased supply of oxygen may lead to false conclusions, especially by considering that their regulation is also posttranscriptional through the action of PHD and VHL. Later during gestation, when fetal-placental unit provides satisfactory quantities of O2, HIFs are downregulated by decreased expression or degradation. In pathological situations, however, it is probable that this model is disturbed and the maintenance of decreased oxygenation affects the regulating action of these factors. Thus exists a change/imbalance in the expression of genes related with processes such as angiogenesis (VEGF, PLGF, PDGF, EPO, NOS2, FLT1 etc), metabolism (aldolase, hexokinase, pyrouvic kinase, lactic dehydrogonase etc) and cellular cycle (IGF, p21, p35srj etc). These changes may

Numerous factors are thought to play a role in normal vascular adaptation to implantation. The VEGFs are specific stimulators of vascular permeability, as well as vascular endothelial cell protease production and migration, all of which are critical components of the angiogenic process [Folkman et al., 1987] Vascular endothelial growth factor also stimulate angiogenesis in a variety of in vivo and in vitro models [Klagsbrun et al., 1991]. The increased expression of VEGF-A, b-FGF, and eNOS that we have found in IUGR placentas may promote increased endothelial cell proliferation and migration and pathological

VEGF, placental growth factor (PlGF), angiopoietins (Ang-1 and Ang-2) are involved not only in the regulation of vascular development and in remodeling during placentation, but also act as growth factors for driving growth and differentiation processes such as invasion. It has been hypothesized that an impairment of trophoblast invasion and a failure of spiral artery remodeling could have a role in the development of PE and FGR [Wulff et al., 2003]. Vascular endothelial growth factor-A (VEGF-A) and placental growth factor (PlGF) are probably the best-studied factors. VEGF interacts with VEGFR-1 (Flt-1) and VEGFR-2 (KDR) to promote endothelial cell proliferation, cell migration, and vascular permeability. PlGF shares biochemical and functional features with VEGF and interacts with VEGFR-1 (Flt-1). PlGF and VEGF-A have synergistic effects regarding angiogenesis, but vessels induced by PlGF are more mature and stable than vessels induced byVEGF-A [Chung et al., 2004]. PlGF is abundantly expressed in the human placenta. Both VEGF-A and PlGF may be important paracrine regulators of decidual angiogenesis and autocrine mediators of trophoblast

A second family of growth factors, the angiopoietins, is also known for their regulating capacities regarding angiogenesis. Angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) bind with equal affinity to their receptor TIE-2, but have different functions. Ang-1 maintains vessel integrity and plays a role in the later stages of vascular remodeling [Geva et al., 2000]. Ang-2 is a functional antagonist of Ang-1 and leads to loosening of cell–cell interactions and allows access to angiogenic inducers like VEGF. Coexpression of VEGF and Ang-2 induces angiogenesis, but Ang-2 results in vascular regression in the absence of angiogenic signals. Ang-1 and Ang-2 have

both been detected in decidual and placental tissues [Asahara et al., 1998].

produce clinical signs and symptoms of FGR or preeclampsia or of both of them.

**3. Angiogenetic growth factors in FGR** 

angiogenesis [Kinzler et al., 2008].

function [Sherer et al., 2001].

A successful pregnancy outcome depends on the proper development of the fetoplacental vasculature in the villous core, which begins with the infiltration of cytotrophoblast in the endometrium and is completed in conjunction with the spiral arteries. It is widely accepted that shallow trophoblast invasion can lead to fetal hypoxia and impaired growth. The proper and timely proliferation and differentiation of the villous cytotrophoblast stem cells, which are controlled by hypoxia, are crucial for adequate placentation and initiation of angiogenetic pathways. Numerous factors are thought to play a role in normal vascular adaptation to implantation. There is strong evidence that abnormal levels of angiogenic and antiangiogenic growth factors could in part be responsible for the pathophysiology associated with pregnancies complicated by FGR.

### **5. References**


**12** 

*Spain* 

*1Hospital de Jerez de la Frontera* 

*2Hospital Juan Grande* 

**The External Version in Modern Obstetrics** 

The incidence of breech presentation is 3-4% (Enkin et al 1995). It is still debated what is the best performance. In particular, both the role of the external cephalic version and the birth

In contrast to cephalic presentations, breech presentations has a higher mortality and morbidity due to the associated incidence of prematurity, congenital malformations or intrapartum asphyxia. Thus, many efforts have been made in order to establish the best performance regarding the birth type: either vaginal delivery (in those women selected after evaluating different fetal and pelvic parameters) or the elective caesarian. On the other hand, the external version can be also considered. (American College Obstetricians and gynecologist [ACOG], 2001). It aims to avoid the vaginal delivery or caesarian complications

Breech presentation is an independent factor associated with higher morbidity (Royal College of Obstetricians and Gynaecologists [RCOG], 2006). In fact, a high prevalence rate in children disabilities after breech presentation (16%) has been registered both in vaginal and

Traditionally, there has always been a general agreement on the preference of caesarian delivery instead of a elective vaginal delivery in case of breech babies in the following circumstances: feet first, large fetus, intrapartum risk of loss of fetal well-being, congenital malformations (meaning a mechanical problem for a vaginal delivery) or in case of

Some obstetricians advocate caesarean intervention in order to reduce the perinatal risks associated with breech presentation. Unfortunately this is based on their personal experience, medical legal aspects and non-randomized studies. Nevertheless, other obstetricians still advocate for vaginal delivery in selected cases, as it may reduce the maternal morbidity and the use of medical resources. In 2000, the results of a multicentric and randomized clinical study conducted by *Hannah* et al. in collaboration with *The Term Breech Trial* were published in *The Lancet* (Hannah et al, 2000). In this study, the caesarean delivery was highly recommended in breech babies at term. The Cochrane database also published a meta-analysis including *Hannah*'s project (Hofmeyr

**1. Introduction** 

type have been extensively debated.

caesarean delivery (Danielian et al, 1996).

inexperienced obstetricians.

by turning a breech presentation into a cephalic presentation.

Esther Fandiño García1 And Juan Carlos Delgado Herrero2

Folkman J, Shing Y. Angiogenesis. J Biol Chem 1992;267:10931–10934

