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Maternally sequestered therapeutic polypeptides - a new approach for the management of preeclampsia.

Bidwell GL, George EM - Front Pharmacol (2014)

Bottom Line: While the molecular mechanisms are becoming clearer, translating that knowledge into effective therapeutics has proven elusive.This prevents fetal exposure and potential developmental effects.The therapeutics designed will target known pathogenic pathways, and the ELP carrier could prove to be a versatile delivery system for administration of a variety of therapeutics during pregnancy.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, The University of Mississippi Medical Center Jackson, MS, USA ; Department of Biochemistry, The University of Mississippi Medical Center Jackson, MS, USA.

ABSTRACT
The last several decades have seen intensive research into the molecular mechanisms underlying the symptoms of preeclampsia. While the underlying cause of preeclampsia is believed to be defective placental development and resulting placental ischemia, it is only recently that the links between the ischemic placenta and maternal symptomatic manifestation have been elucidated. Several different pathways have been implicated in the development of the disorder; most notably production of the anti-angiogenic protein sFlt-1, induction of auto-immunity and inflammation, and production of reactive oxygen species. While the molecular mechanisms are becoming clearer, translating that knowledge into effective therapeutics has proven elusive. Here we describe a number of peptide based therapies we have developed to target theses pathways, and which are currently being tested in preclinical models. These therapeutics are based on a synthetic polymeric carrier elastin-like polypeptide (ELP), which can be synthesized in various sequences and sizes to stabilize the therapeutic peptide and avoid crossing the placental interface. This prevents fetal exposure and potential developmental effects. The therapeutics designed will target known pathogenic pathways, and the ELP carrier could prove to be a versatile delivery system for administration of a variety of therapeutics during pregnancy.

No MeSH data available.


Related in: MedlinePlus

The maternal symptoms of preeclampsia arise through multiple molecular mechanisms. Improper placentation leads to placental ischemia. As a direct result, the placenta produces the anti-angiogenic protein sFlt-1, inflammatory cytokines, and increased reactive oxygen species (ROS); as well as increased production of the agonistic AT-1 receptor autoantibody (AT1-AA). The maternal vasculature, including that in the kidneys, is exposed to decreased VEGF signaling and inflammatory mechanisms which cause endothelial dysfunction, marked by overproduction of the vasoconstrictor endothelin-1 (ET-1). In the kidneys, total peripheral resistance (TPR) increases, renal blood flow (RBF) and glomerular filtration rate (GFR) decrease, and maternal hypertension is the end result.
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Figure 1: The maternal symptoms of preeclampsia arise through multiple molecular mechanisms. Improper placentation leads to placental ischemia. As a direct result, the placenta produces the anti-angiogenic protein sFlt-1, inflammatory cytokines, and increased reactive oxygen species (ROS); as well as increased production of the agonistic AT-1 receptor autoantibody (AT1-AA). The maternal vasculature, including that in the kidneys, is exposed to decreased VEGF signaling and inflammatory mechanisms which cause endothelial dysfunction, marked by overproduction of the vasoconstrictor endothelin-1 (ET-1). In the kidneys, total peripheral resistance (TPR) increases, renal blood flow (RBF) and glomerular filtration rate (GFR) decrease, and maternal hypertension is the end result.

Mentions: While a great deal of research has begun to elucidate the molecular and physiological mechanisms which are responsible for the maternal symptoms, the initiating causes remain unclear. What has become generally accepted is that the disorder is closely linked to defects at the maternal/fetal interface, particularly in the remodeling of the maternal spiral arteries which supply the blood flow to the placenta (Khong and Brosens, 2011). During gestation, the developing fetus requires copious amounts of blood flow to the placenta to allow for adequate exchange of nutrients and wastes between the maternal and fetal circulations. To ensure adequate delivery of blood, the maternal spiral arteries of the uterus undergo a dramatic remodeling. Fetally derived cytotrophoblasts invade the maternal vessels, displace the endothelium, and convert the normally small diameter, low capacitance vessels into dilated high capacitance vessels. Clues that the placenta was central to the etiology of preeclampsia came from case reports showing that delivery of the fetus alone was insufficient to remit the disease symptoms, and that delivery of the placenta was crucial for resolution (Shembrey and Noble, 1995). Early histological examination of placentas from preeclampsia patients suggested that the remodeling of these arteries in preeclampsia patients was deficient, with only very shallow trophoblast invasion and arterial remodeling. This led to the idea that in preeclampsia, the placenta-which even in normal pregnancy is relatively hypoxic-receives inadequate blood flow and in consequence experiences chronic hypoxia and ischemia. Indeed, a host of studies over the last 15 years have strongly implicated placental ischemia as a central factor in the manifestation of preeclampsia. Research into the molecular links between chronic placental ischemia and the symptomatic phase of the disorder continue, but several pathways have been intensively investigated and validated. This includes production of the anti-angiogenic protein soluble fms-like tyrosine kinase-1 (sFlt-1), production of inflammatory cytokines such as TNFα, and increased production of oxidative stress in the placenta and maternal vasculature (Figure 1).


Maternally sequestered therapeutic polypeptides - a new approach for the management of preeclampsia.

Bidwell GL, George EM - Front Pharmacol (2014)

The maternal symptoms of preeclampsia arise through multiple molecular mechanisms. Improper placentation leads to placental ischemia. As a direct result, the placenta produces the anti-angiogenic protein sFlt-1, inflammatory cytokines, and increased reactive oxygen species (ROS); as well as increased production of the agonistic AT-1 receptor autoantibody (AT1-AA). The maternal vasculature, including that in the kidneys, is exposed to decreased VEGF signaling and inflammatory mechanisms which cause endothelial dysfunction, marked by overproduction of the vasoconstrictor endothelin-1 (ET-1). In the kidneys, total peripheral resistance (TPR) increases, renal blood flow (RBF) and glomerular filtration rate (GFR) decrease, and maternal hypertension is the end result.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4155872&req=5

Figure 1: The maternal symptoms of preeclampsia arise through multiple molecular mechanisms. Improper placentation leads to placental ischemia. As a direct result, the placenta produces the anti-angiogenic protein sFlt-1, inflammatory cytokines, and increased reactive oxygen species (ROS); as well as increased production of the agonistic AT-1 receptor autoantibody (AT1-AA). The maternal vasculature, including that in the kidneys, is exposed to decreased VEGF signaling and inflammatory mechanisms which cause endothelial dysfunction, marked by overproduction of the vasoconstrictor endothelin-1 (ET-1). In the kidneys, total peripheral resistance (TPR) increases, renal blood flow (RBF) and glomerular filtration rate (GFR) decrease, and maternal hypertension is the end result.
Mentions: While a great deal of research has begun to elucidate the molecular and physiological mechanisms which are responsible for the maternal symptoms, the initiating causes remain unclear. What has become generally accepted is that the disorder is closely linked to defects at the maternal/fetal interface, particularly in the remodeling of the maternal spiral arteries which supply the blood flow to the placenta (Khong and Brosens, 2011). During gestation, the developing fetus requires copious amounts of blood flow to the placenta to allow for adequate exchange of nutrients and wastes between the maternal and fetal circulations. To ensure adequate delivery of blood, the maternal spiral arteries of the uterus undergo a dramatic remodeling. Fetally derived cytotrophoblasts invade the maternal vessels, displace the endothelium, and convert the normally small diameter, low capacitance vessels into dilated high capacitance vessels. Clues that the placenta was central to the etiology of preeclampsia came from case reports showing that delivery of the fetus alone was insufficient to remit the disease symptoms, and that delivery of the placenta was crucial for resolution (Shembrey and Noble, 1995). Early histological examination of placentas from preeclampsia patients suggested that the remodeling of these arteries in preeclampsia patients was deficient, with only very shallow trophoblast invasion and arterial remodeling. This led to the idea that in preeclampsia, the placenta-which even in normal pregnancy is relatively hypoxic-receives inadequate blood flow and in consequence experiences chronic hypoxia and ischemia. Indeed, a host of studies over the last 15 years have strongly implicated placental ischemia as a central factor in the manifestation of preeclampsia. Research into the molecular links between chronic placental ischemia and the symptomatic phase of the disorder continue, but several pathways have been intensively investigated and validated. This includes production of the anti-angiogenic protein soluble fms-like tyrosine kinase-1 (sFlt-1), production of inflammatory cytokines such as TNFα, and increased production of oxidative stress in the placenta and maternal vasculature (Figure 1).

Bottom Line: While the molecular mechanisms are becoming clearer, translating that knowledge into effective therapeutics has proven elusive.This prevents fetal exposure and potential developmental effects.The therapeutics designed will target known pathogenic pathways, and the ELP carrier could prove to be a versatile delivery system for administration of a variety of therapeutics during pregnancy.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology, The University of Mississippi Medical Center Jackson, MS, USA ; Department of Biochemistry, The University of Mississippi Medical Center Jackson, MS, USA.

ABSTRACT
The last several decades have seen intensive research into the molecular mechanisms underlying the symptoms of preeclampsia. While the underlying cause of preeclampsia is believed to be defective placental development and resulting placental ischemia, it is only recently that the links between the ischemic placenta and maternal symptomatic manifestation have been elucidated. Several different pathways have been implicated in the development of the disorder; most notably production of the anti-angiogenic protein sFlt-1, induction of auto-immunity and inflammation, and production of reactive oxygen species. While the molecular mechanisms are becoming clearer, translating that knowledge into effective therapeutics has proven elusive. Here we describe a number of peptide based therapies we have developed to target theses pathways, and which are currently being tested in preclinical models. These therapeutics are based on a synthetic polymeric carrier elastin-like polypeptide (ELP), which can be synthesized in various sequences and sizes to stabilize the therapeutic peptide and avoid crossing the placental interface. This prevents fetal exposure and potential developmental effects. The therapeutics designed will target known pathogenic pathways, and the ELP carrier could prove to be a versatile delivery system for administration of a variety of therapeutics during pregnancy.

No MeSH data available.


Related in: MedlinePlus