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Vikas P. Sukhatme

Bio: Vikas P. Sukhatme is an academic researcher from Emory University. The author has contributed to research in topics: Gene expression & Angiogenesis. The author has an hindex of 100, co-authored 317 publications receiving 39027 citations. Previous affiliations of Vikas P. Sukhatme include Stanford University & University of Pennsylvania.


Papers
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Journal ArticleDOI
TL;DR: It is confirmed that placental soluble fms-like tyrosine kinase 1 (sFlt1), an antagonist of VEGF and placental growth factor (PlGF), is upregulated in preeclampsia, leading to increased systemic levels of sFlt 1 that fall after delivery, and observations suggest that excess circulating sFelt1 contributes to the pathogenesis of preeClampsia.
Abstract: Preeclampsia, a syndrome affecting 5% of pregnancies, causes substantial maternal and fetal morbidity and mortality. The pathophysiology of preeclampsia remains largely unknown. It has been hypothesized that placental ischemia is an early event, leading to placental production of a soluble factor or factors that cause maternal endothelial dysfunction, resulting in the clinical findings of hypertension, proteinuria, and edema. Here, we confirm that placental soluble fms-like tyrosine kinase 1 (sFlt1), an antagonist of VEGF and placental growth factor (PlGF), is upregulated in preeclampsia, leading to increased systemic levels of sFlt1 that fall after delivery. We demonstrate that increased circulating sFlt1 in patients with preeclampsia is associated with decreased circulating levels of free VEGF and PlGF, resulting in endothelial dysfunction in vitro that can be rescued by exogenous VEGF and PlGF. Additionally, VEGF and PlGF cause microvascular relaxation of rat renal arterioles in vitro that is blocked by sFlt1. Finally, administration of sFlt1 to pregnant rats induces hypertension, proteinuria, and glomerular endotheliosis, the classic lesion of preeclampsia. These observations suggest that excess circulating sFlt1 contributes to the pathogenesis of preeclampsia.

3,613 citations

Journal ArticleDOI
TL;DR: Alterations in the levels of sFlt-1 and free PlGF were greater in women with an earlier onset of preeclampsia and in women in whom preeClampsia was associated with a small-for-gestational-age infant.
Abstract: Background The cause of preeclampsia remains unclear. Limited data suggest that excess circulating soluble fms-like tyrosine kinase 1 (sFlt-1), which binds placental growth factor (PlGF) and vascul...

3,148 citations

Journal ArticleDOI
TL;DR: A novel placenta-derived soluble TGF-β coreceptor, endoglin (sEng), which is elevated in the sera of preeclamptic individuals, correlates with disease severity and falls after delivery, suggest that sEng may act in concert with sFlt1 to induce severe preeclampsia.
Abstract: Preeclampsia is a pregnancy-specific hypertensive syndrome that causes substantial maternal and fetal morbidity and mortality. Maternal endothelial dysfunction mediated by excess placenta-derived soluble VEGF receptor 1 (sVEGFR1 or sFlt1) is emerging as a prominent component in disease pathogenesis. We report a novel placenta-derived soluble TGF-beta coreceptor, endoglin (sEng), which is elevated in the sera of preeclamptic individuals, correlates with disease severity and falls after delivery. sEng inhibits formation of capillary tubes in vitro and induces vascular permeability and hypertension in vivo. Its effects in pregnant rats are amplified by coadministration of sFlt1, leading to severe preeclampsia including the HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome and restriction of fetal growth. sEng impairs binding of TGF-beta1 to its receptors and downstream signaling including effects on activation of eNOS and vasodilation, suggesting that sEng leads to dysregulated TGF-beta signaling in the vasculature. Our results suggest that sEng may act in concert with sFlt1 to induce severe preeclampsia.

1,731 citations

Journal ArticleDOI
08 Apr 1988-Cell
TL;DR: Sequence analysis of murine Egr-1 cDNA predicts a protein with three DNA binding zinc fingers, and results suggest that EGR1 may function as a transcriptional regulator in diverse biological processes.

1,233 citations

Journal ArticleDOI
TL;DR: It is confirmed that placental soluble fms-like tyrosine kinase 1 (sFlt1), an antagonist of VEGF and placental growth factor (PlGF), is upregulated in preeclampsia, leading to increased systemic levels of sFlt 1 that fall after delivery, and observations suggest that excess circulating sFelt1 contributes to the pathogenesis of preeClampsia.
Abstract: Numerous explanations of the endothelial dysfunction that characterizes preeclampsia have been advanced This pathophysiological study examined the hypothesis that placental ischemia occurs at an early stage and promotesplacental production of a soluble factor that leads to maternal endothelial dysfunction and its clinical sequelae, hypertension, proteinuria, and edema Profiles of gene expression in placental tissue were obtained in samples from women with and without preeclampsia Soluble fins-like tyrosine kinase 1 (sFlt1) mRNA has been found to be upregulated in preeclamptic placentas It is a splice variant of the vascular endothelial growth factor (VEGF) receptor that acts as a potent VEGF and placental growth factor (PlGF) antagonist Circumstantial evidence suggests that antagonism of VEGF could contribute to hypertension and proteinuria in view of the fact that the growth factor helps to reduce vascular tone and blood pressure The presence of increased amounts of mRNA for placental sFlt1 was confirmed, Both sFlt1 and Flt1 messages were upregulated in preeciamptic placentas Studies in 32 pregnant women showed that total serum sFlt1 was nearly 5 times higher in those with severe preeclampsia than in normotensive women, and this difference was not explained by earlier gestational age Serum levels of free VEDGF and PlGF, measured by enzyme-linked immunosorbent assay, were significantly reduced in the presence of recombinant sFltl Angiogenesis, as reflected by endothelial tube formation, was inhibited by serum from women with preeclampsia, and an analogous effect was noted in vitro when adding sFlt1 to serum from normotensive women Adding VEGF and PlGF to preeclamptic serum restored tube formation Studies based on an in vitro assay for microvascular reactivity showed that sFltl by itself did not cause significant vasoconstriction, but it did block the dose-dependent increase in vasodilation produced by VEGF or PlGF Recombinant adenovirus encoding the murine sFltl gene product produced significant hypertension and heavy albuminuria when injected into pregnant rats Similar effects were noted in nonpregnant animals In pregnant rats treated with sFltl, renal glomeruli enlarged and capillary loops were occluded by swollen hypertrophied endocapillary cells Similar renal lesions developed in sFlk1-treated nonpregnant rats These findings suggest that excessive placental production of sFlt1 contributes to hypertension, proteinuria, and glomerular endotheliosis in preeclamptic women Antagonizing these effects could be a promising approach to treating these patients

1,003 citations


Cited by
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Journal ArticleDOI
TL;DR: Vascular endothelial growth factor (VEGF) is a key regulator of physiological angiogenesis during embryogenesis, skeletal growth and reproductive functions and is implicated in pathologicalAngiogenesis associated with tumors, intraocular neovascular disorders and other conditions.
Abstract: Vascular endothelial growth factor (VEGF) is a key regulator of physiological angiogenesis during embryogenesis, skeletal growth and reproductive functions. VEGF has also been implicated in pathological angiogenesis associated with tumors, intraocular neovascular disorders and other conditions. The biological effects of VEGF are mediated by two receptor tyrosine kinases (RTKs), VEGFR-1 and VEGFR-2, which differ considerably in signaling properties. Non-signaling co-receptors also modulate VEGF RTK signaling. Currently, several VEGF inhibitors are undergoing clinical testing in several malignancies. VEGF inhibition is also being tested as a strategy for the prevention of angiogenesis, vascular leakage and visual loss in age-related macular degeneration.

8,942 citations

Journal ArticleDOI
07 Oct 1994-Science
TL;DR: A strong candidate for the 17q-linked BRCA1 gene, which influences susceptibility to breast and ovarian cancer, has been identified by positional cloning methods.
Abstract: A strong candidate for the 17q-linked BRCA1 gene, which influences susceptibility to breast and ovarian cancer, has been identified by positional cloning methods. Probable predisposing mutations have been detected in five of eight kindreds presumed to segregate BRCA1 susceptibility alleles. The mutations include an 11-base pair deletion, a 1-base pair insertion, a stop codon, a missense substitution, and an inferred regulatory mutation. The BRCA1 gene is expressed in numerous tissues, including breast and ovary, and encodes a predicted protein of 1863 amino acids. This protein contains a zinc finger domain in its amino-terminal region, but is otherwise unrelated to previously described proteins. Identification of BRCA1 should facilitate early diagnosis of breast and ovarian cancer susceptibility in some individuals as well as a better understanding of breast cancer biology.

6,118 citations

Journal ArticleDOI
TL;DR: The establishment of a vascular supply is required for organ development and differentiation as well as for tissue repair and reproductive functions in the adult.
Abstract: The establishment of a vascular supply is required for organ development and differentiation as well as for tissue repair and reproductive functions in the adult1 Neovascularization (angiogenesis) is also implicated in the pathogenesis of a number of disorders These include: proliferative retinopathies, age-related macular degeneration, tumors, rheumatoid arthritis, and psoriasis1,2 A strong correlation has been noted between density of microvessels in primary breast cancers and their nodal metastases and patient survival3 Similarly, a correlation has been reported between vascularity and invasive behavior in several other tumors4–6

4,603 citations

Journal ArticleDOI
TL;DR: Fibroblasts are a key determinant in the malignant progression of cancer and represent an important target for cancer therapies.
Abstract: Tumours are known as wounds that do not heal - this implies that cells that are involved in angiogenesis and the response to injury, such as endothelial cells and fibroblasts, have a prominent role in the progression, growth and spread of cancers. Fibroblasts are associated with cancer cells at all stages of cancer progression, and their structural and functional contributions to this process are beginning to emerge. Their production of growth factors, chemokines and extracellular matrix facilitates the angiogenic recruitment of endothelial cells and pericytes. Fibroblasts are therefore a key determinant in the malignant progression of cancer and represent an important target for cancer therapies.

4,232 citations

Journal ArticleDOI
TL;DR: Molecular insights into the formation of new blood vessels are being generated at a rapidly increasing pace, offering new therapeutic opportunities that are currently being evaluated.
Abstract: Blood vessels constitute the first organ in the embryo and form the largest network in our body but, sadly, are also often deadly. When dysregulated, the formation of new blood vessels contributes to numerous malignant, ischemic, inflammatory, infectious and immune disorders. Molecular insights into these processes are being generated at a rapidly increasing pace, offering new therapeutic opportunities that are currently being evaluated.

4,137 citations