June 9th 06, 11:57 PM
http://www.eurekalert.org/pub_releases/2006-06/bidm-rip060206.php
RESEARCHERS IDENTIFY PROTEIN ASSOCIATED WITH SEVERE PREECLAMPSIA
Study finds that the endoglin protein acts together with sFlt1 to
rapidly escalate disease
BOSTON -- Building on their earlier discovery which found that elevated
levels of the sFlt1 placental protein leads to the onset of
preeclampsia, researchers at Beth Israel Deaconess Medical Center
(BIDMC), in collaboration with a research team from The Hospital for
Sick Children, Toronto, have identified a second protein which, in
combination with sFlt1, escalates preeclampsia to a severe - and
life-threatening -- state.
These new findings, reported in the June 4, 2006 on-line issue of
Nature Medicine, provide another critical piece of information about
this puzzling disease, which complicates five percent of all
pregnancies worldwide and is a major cause of maternal and fetal
mortality, particularly in developing nations.
"Preeclampsia typically develops in the third trimester of pregnancy
and is characterized by high blood pressure, edema and protein in the
urine," explains the study's senior author S. Ananth Karumanchi,
MD, a nephrologist in the Center for Vascular Biology at BIDMC and
Assistant Professor of Medicine, Obstetrics and Gynecology at Harvard
Medical School.
Three years ago, Karumanchi and his colleagues demonstrated that the
placenta plays a central role in the course of these events, and that
elevated levels of a placental protein called sFlt1 (soluble fms-like
tyrosine kinase) are key to the onset of the disease.
However, for unknown reasons, a subset of preeclampsia patients will go
on to experience severe preeclampsia - a group of dramatically
escalated symptoms characterized by a sudden, massive rise in blood
pressure, which can lead to the onset of seizures, as well as the
development of fetal growth restriction and the HELLP syndrome. HELLP,
which stands for hemolysis, elevated liver enzymes and low platelets,
indicates that the mother's liver and blood-clotting systems are not
functioning properly, and the health of both mother and infant are in
serious danger.
"During the course of our previous experiments [to confirm the role
of sFlt1 in the disease] we observed that although all of the animals
treated with sFlt1 exhibited telltale symptoms of hypertension and
proteinuria, they did not all go on to develop symptoms of the HELLP
syndrome," notes Karumanchi.
"We, therefore, hypothesized that other placenta-derived proteins
must be acting jointly with sFlt1 to induce vascular damage and
escalate the disease to its severe form."
Using microarray analysis of human placental specimens from patients
with preeclampsia, Karumanchi and his coauthors observed that a protein
known as endoglin was significantly upregulated. (Endoglin was
discovered 20 years ago in the laboratory of study collaborator
Michelle Letarte at The Hospital for Sick Children, Toronto.) A
co-receptor for transforming growth factor beta family proteins,
endoglin is expressed on endothelial cells lining the blood vessels,
and thereby plays an important role in maintaining the health and
integrity of the vascular system.
"Our further investigations revealed that the extracellular region of
the endoglin protein is shed into maternal circulation," explains
Karumanchi. "We discovered that this shed form -- referred to as
'soluble endoglin' - was circulating in very high quantities
among women with severe forms of preeclampsia."
In order to understand the protein's biological role, the
investigators next administered soluble endoglin to pregnant rats;
their results showed that this protein was indeed amplifying the
vascular damage mediated by sFlt1, resulting in the symptoms of severe
preeclampsia.
"What is apparently happening is that both sFlt1 and soluble endoglin
are inhibiting the functions of two angiogenic growth factors -
vascular endothelial growth factor [VEGF] and transforming growth
factor beta," explains Karumanchi. "The diminished signaling of
these growth factors in the vasculature adversely affects the health of
the mother's small blood vessels." The result is the onset of
severe preeclampsia and its dangerous consequences for both mother and
infant.
"We believe that these latest findings will have important diagnostic
and therapeutic implications for the management of this disease,"
says Karumanchi.
Adds Benjamin Sachs, MBBS, DPH, Chief of the Department of Obstetrics
and Gynecology at BIDMC, "Preeclampsia affects 200,000 pregnancies a
year in the United States and often leads to premature births. Severe
preeclampsia is one of the world's leading causes of maternal and
fetal mortality and poses a particular risk to women in developing
countries. This new information provides us with another key piece of
evidence as we work toward developing the means to diagnose, and
eventually treat, this disease."
Study coauthors include BIDMC investigators Shivalingappa Venkatesha,
PhD, Chun Lam, MD, Jun-ichi Hanai, MD, PhD, Tadanori Mammoto, MD, PhD,
Yuval Bdolah, MD, Kee-Hak Lim, MD, Hai-Tao Yuan, MD, Towia Libermann,
PhD, Isaac Stillman, MD, Franklin Epstein, MD, Frank Sellke, MD, PhD,
and Vikas Sukhatme, MD, PhD; Mourad Toporsian, PhD, and Michelle
Letarte, PhD, of The Hospital for Sick Children, University of Toronto,
Ontario, Canada; Yeon Kim, MD, and Roberto Romero, MD, of the National
Institute of Child Health and Human Development, Bethesda, Maryland;
Drucilla Roberts, MD, PhD, of Massachusetts General Hospital; and
Patricia D'Amore, PhD, of Schepens Eye Research Institute, Boston.
This study was funded, in part, by grants from the National Institutes
of Health and the Heart and Stroke Foundation of Ontario.
BIDMC has filed patents on methods of diagnosing and treating
preeclampsia.
Beth Israel Deaconess Medical Center is a patient care, teaching and
research affiliate of Harvard Medical School and ranks fourth among
independent hospitals nationwide in National Institutes of Health
funding. BIDMC is clinically affiliated with the Joslin Diabetes Center
and is a research partner of the Dana-Farber /Harvard Cancer Center.
BIDMC is the official hospital of the Boston Red Sox. For more
information, visit www.bidmc.harvard.edu.
--
C, mama to three year old nursling
RESEARCHERS IDENTIFY PROTEIN ASSOCIATED WITH SEVERE PREECLAMPSIA
Study finds that the endoglin protein acts together with sFlt1 to
rapidly escalate disease
BOSTON -- Building on their earlier discovery which found that elevated
levels of the sFlt1 placental protein leads to the onset of
preeclampsia, researchers at Beth Israel Deaconess Medical Center
(BIDMC), in collaboration with a research team from The Hospital for
Sick Children, Toronto, have identified a second protein which, in
combination with sFlt1, escalates preeclampsia to a severe - and
life-threatening -- state.
These new findings, reported in the June 4, 2006 on-line issue of
Nature Medicine, provide another critical piece of information about
this puzzling disease, which complicates five percent of all
pregnancies worldwide and is a major cause of maternal and fetal
mortality, particularly in developing nations.
"Preeclampsia typically develops in the third trimester of pregnancy
and is characterized by high blood pressure, edema and protein in the
urine," explains the study's senior author S. Ananth Karumanchi,
MD, a nephrologist in the Center for Vascular Biology at BIDMC and
Assistant Professor of Medicine, Obstetrics and Gynecology at Harvard
Medical School.
Three years ago, Karumanchi and his colleagues demonstrated that the
placenta plays a central role in the course of these events, and that
elevated levels of a placental protein called sFlt1 (soluble fms-like
tyrosine kinase) are key to the onset of the disease.
However, for unknown reasons, a subset of preeclampsia patients will go
on to experience severe preeclampsia - a group of dramatically
escalated symptoms characterized by a sudden, massive rise in blood
pressure, which can lead to the onset of seizures, as well as the
development of fetal growth restriction and the HELLP syndrome. HELLP,
which stands for hemolysis, elevated liver enzymes and low platelets,
indicates that the mother's liver and blood-clotting systems are not
functioning properly, and the health of both mother and infant are in
serious danger.
"During the course of our previous experiments [to confirm the role
of sFlt1 in the disease] we observed that although all of the animals
treated with sFlt1 exhibited telltale symptoms of hypertension and
proteinuria, they did not all go on to develop symptoms of the HELLP
syndrome," notes Karumanchi.
"We, therefore, hypothesized that other placenta-derived proteins
must be acting jointly with sFlt1 to induce vascular damage and
escalate the disease to its severe form."
Using microarray analysis of human placental specimens from patients
with preeclampsia, Karumanchi and his coauthors observed that a protein
known as endoglin was significantly upregulated. (Endoglin was
discovered 20 years ago in the laboratory of study collaborator
Michelle Letarte at The Hospital for Sick Children, Toronto.) A
co-receptor for transforming growth factor beta family proteins,
endoglin is expressed on endothelial cells lining the blood vessels,
and thereby plays an important role in maintaining the health and
integrity of the vascular system.
"Our further investigations revealed that the extracellular region of
the endoglin protein is shed into maternal circulation," explains
Karumanchi. "We discovered that this shed form -- referred to as
'soluble endoglin' - was circulating in very high quantities
among women with severe forms of preeclampsia."
In order to understand the protein's biological role, the
investigators next administered soluble endoglin to pregnant rats;
their results showed that this protein was indeed amplifying the
vascular damage mediated by sFlt1, resulting in the symptoms of severe
preeclampsia.
"What is apparently happening is that both sFlt1 and soluble endoglin
are inhibiting the functions of two angiogenic growth factors -
vascular endothelial growth factor [VEGF] and transforming growth
factor beta," explains Karumanchi. "The diminished signaling of
these growth factors in the vasculature adversely affects the health of
the mother's small blood vessels." The result is the onset of
severe preeclampsia and its dangerous consequences for both mother and
infant.
"We believe that these latest findings will have important diagnostic
and therapeutic implications for the management of this disease,"
says Karumanchi.
Adds Benjamin Sachs, MBBS, DPH, Chief of the Department of Obstetrics
and Gynecology at BIDMC, "Preeclampsia affects 200,000 pregnancies a
year in the United States and often leads to premature births. Severe
preeclampsia is one of the world's leading causes of maternal and
fetal mortality and poses a particular risk to women in developing
countries. This new information provides us with another key piece of
evidence as we work toward developing the means to diagnose, and
eventually treat, this disease."
Study coauthors include BIDMC investigators Shivalingappa Venkatesha,
PhD, Chun Lam, MD, Jun-ichi Hanai, MD, PhD, Tadanori Mammoto, MD, PhD,
Yuval Bdolah, MD, Kee-Hak Lim, MD, Hai-Tao Yuan, MD, Towia Libermann,
PhD, Isaac Stillman, MD, Franklin Epstein, MD, Frank Sellke, MD, PhD,
and Vikas Sukhatme, MD, PhD; Mourad Toporsian, PhD, and Michelle
Letarte, PhD, of The Hospital for Sick Children, University of Toronto,
Ontario, Canada; Yeon Kim, MD, and Roberto Romero, MD, of the National
Institute of Child Health and Human Development, Bethesda, Maryland;
Drucilla Roberts, MD, PhD, of Massachusetts General Hospital; and
Patricia D'Amore, PhD, of Schepens Eye Research Institute, Boston.
This study was funded, in part, by grants from the National Institutes
of Health and the Heart and Stroke Foundation of Ontario.
BIDMC has filed patents on methods of diagnosing and treating
preeclampsia.
Beth Israel Deaconess Medical Center is a patient care, teaching and
research affiliate of Harvard Medical School and ranks fourth among
independent hospitals nationwide in National Institutes of Health
funding. BIDMC is clinically affiliated with the Joslin Diabetes Center
and is a research partner of the Dana-Farber /Harvard Cancer Center.
BIDMC is the official hospital of the Boston Red Sox. For more
information, visit www.bidmc.harvard.edu.
--
C, mama to three year old nursling