BADERC Welcome

Patricia D'Amore, Ph.D.

Regulation of Vascular Development and Growth

Research in the D'Amore laboratory focuses on the growth and maintenance of the microvasculature. This work is relevant to the retinal microangiopathies that occur as a complication of diabetes, including aspects of background diabetic retinopathy such as increased vascular permeability and pericyte dropout as well as the neovascularization that characterizes later stages of diabetic retinopathy. The studies are focused in two general areas: (1) cell-cell interactions and (2) the role and regulation of vascular endothelial growth factor isoforms.

1. Cell-Cell Interactions. The microvasculature consists of two cell types: the endothelial cell, which forms the capillary tube; and the pericyte, which is associated with the abluminal endothelial surface. Using a variety of co-culture systems, we have been examining the nature of the interactions between endothelial cells and pericytes, as well as the physiologic relevance of these interactions. Upon contact between the two cell types, the mesenchymal cells are induced to differentiated to a pericyte/smooth muscle lineage. This process is mediated, at least in part, by the activation of TGF-ß in the co-cultures. Recent in vivo work indicates that neutralization of TGFß in the adult leads to a break down of the blood retinal barrier. Studies have been conducted to elucidate the mechanisms that regulate microvessel assembly. Co-culture of endothelial cells with mesenchymal pericyte precursors has revealed that endothelial cells can recruit undifferentiated mesenchymal cells by secreting PDGF B, which induces the directed migration as well as the proliferation of the precursors. Current work is aimed at elucidating the molecular mechanisms by which pericytes mediate the stability of the microvessels.

2. Vascular Endothelial Growth Factor (VEGF). VEGF is a polypeptide growth factor that is an endothelial mitogen and angiogenic factor. We have previously shown that VEGF levels are increased in a non-human primate model of retinal ischemia-induced iris neovascularization and that administration of soluble VEGF receptor (as a VEGF neutralizing reagent) can block ischemia-induced iris neovascularization. Anti-VEGF therapies, which are in wide treatment for wet macular degeneration, are now being used with success for diabetic macular edema and proliferative diabetic retinopathy. However, our laboratory has demonstrated that in addition to the role that it plays in eye pathology, VEGF is also central to survival of vascular and neural cells of the retina. We have demonstrated that VEGFR2 is expressed not only by vascular endothelial cells but also by Muller cells and photoreceptor cells and that VEGF is produced by astrocytes and by Muller cells. Blockade of VEGF in the adult retina leads to apoptosis of Muller cells and photoreceptors. These results suggest an important autocrine/juxtacrine role for VEGF in the adult retina, which is the subject of current investigations in the lab.

References:

Maruyama K, Asai J, Masaaki Ii, Thorne T, Losordo DW, and D’Amore PA. (2007) Decreased macrophage number and activation lead to reduced lymphatic vessel formation and contribute to impaired diabetic wound healing. Am J Path, 2007, 170:1178-1191.
Ramsauer M, D’Amore PA. (2007) Contextual role for angiopoietins and TGFß1 in blood vessel stabilization. J Cell Sci, , 120:1810-1817.
Sang DN, D’Amore P.A. (2008) Is blockade of vascular endothelial growth factor beneficial for all types of diabetic retinopathy? Diabetologica 51: 1570-1573.
Saint-Geniez M, Maharaj ASR, Walshe TE, Tucker BA, Sekiyama E, et al. (2008) Endogenous VEGF is required for visual function: Evidence for a survival role on Muller cells and photoreceptors. PLoS ONE 3(11): e3554. doi:10.1371/journal.pone.0003554
Walshe TE, Saint-Geniez M, Maharaj ASR, Sekiyama E, Maldonado AE, et al. (2009) TGF-ß is required for vascular barrier function, endothelial survival and homeostasis of the adult microvasculature. PLoS ONE 4(4): e5149. doi:10.1371/journal.pone.0005149






			Patricia D'Amore, Ph.D. Regulation of Vascular Development and Growth Research in the D'Amore laboratory focuses on the growth and maintenance of the microvasculature. This work is relevant to the retinal microangiopathies that occur as a complication of diabetes, including aspects of background diabetic retinopathy such as increased vascular permeability and pericyte dropout as well as the neovascularization that characterizes later stages of diabetic retinopathy. The studies are focused in two general areas: (1) cell-cell interactions and (2) the role and regulation of vascular endothelial growth factor isoforms. 1. Cell-Cell Interactions. The microvasculature consists of two cell types: the endothelial cell, which forms the capillary tube; and the pericyte, which is associated with the abluminal endothelial surface. Using a variety of co-culture systems, we have been examining the nature of the interactions between endothelial cells and pericytes, as well as the physiologic relevance of these interactions. Upon contact between the two cell types, the mesenchymal cells are induced to differentiated to a pericyte/smooth muscle lineage. This process is mediated, at least in part, by the activation of TGF-ß in the co-cultures. Recent in vivo work indicates that neutralization of TGFß in the adult leads to a break down of the blood retinal barrier. Studies have been conducted to elucidate the mechanisms that regulate microvessel assembly. Co-culture of endothelial cells with mesenchymal pericyte precursors has revealed that endothelial cells can recruit undifferentiated mesenchymal cells by secreting PDGF B, which induces the directed migration as well as the proliferation of the precursors. Current work is aimed at elucidating the molecular mechanisms by which pericytes mediate the stability of the microvessels. 2. Vascular Endothelial Growth Factor (VEGF). VEGF is a polypeptide growth factor that is an endothelial mitogen and angiogenic factor. We have previously shown that VEGF levels are increased in a non-human primate model of retinal ischemia-induced iris neovascularization and that administration of soluble VEGF receptor (as a VEGF neutralizing reagent) can block ischemia-induced iris neovascularization. Anti-VEGF therapies, which are in wide treatment for wet macular degeneration, are now being used with success for diabetic macular edema and proliferative diabetic retinopathy. However, our laboratory has demonstrated that in addition to the role that it plays in eye pathology, VEGF is also central to survival of vascular and neural cells of the retina. We have demonstrated that VEGFR2 is expressed not only by vascular endothelial cells but also by Muller cells and photoreceptor cells and that VEGF is produced by astrocytes and by Muller cells. Blockade of VEGF in the adult retina leads to apoptosis of Muller cells and photoreceptors. These results suggest an important autocrine/juxtacrine role for VEGF in the adult retina, which is the subject of current investigations in the lab. References: Maruyama K, Asai J, Masaaki Ii, Thorne T, Losordo DW, and D’Amore PA. (2007) Decreased macrophage number and activation lead to reduced lymphatic vessel formation and contribute to impaired diabetic wound healing. Am J Path, 2007, 170:1178-1191. Ramsauer M, D’Amore PA. (2007) Contextual role for angiopoietins and TGFß1 in blood vessel stabilization. J Cell Sci, , 120:1810-1817. Sang DN, D’Amore P.A. (2008) Is blockade of vascular endothelial growth factor beneficial for all types of diabetic retinopathy? Diabetologica 51: 1570-1573. Saint-Geniez M, Maharaj ASR, Walshe TE, Tucker BA, Sekiyama E, et al. (2008) Endogenous VEGF is required for visual function: Evidence for a survival role on Muller cells and photoreceptors. PLoS ONE 3(11): e3554. doi:10.1371/journal.pone.0003554 Walshe TE, Saint-Geniez M, Maharaj ASR, Sekiyama E, Maldonado AE, et al. (2009) TGF-ß is required for vascular barrier function, endothelial survival and homeostasis of the adult microvasculature. PLoS ONE 4(4): e5149. doi:10.1371/journal.pone.0005149