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Stanley J Wiegand

Publications and source records attributed to Stanley J Wiegand.

At least 19 recordsLinked to original sources
PubMed2006

BDNF: a missing link between sympathetic dysfunction and inflammatory disease?

Nerve growth factor (NGF) plays a role in sympathetic neuron integrity and survival. Brain-derived neurotrophic factor (BDNF) also has trophic effects on sympathetic neurons. We report here the serendipitous finding that co-treatment of hippocampus with BDNF and the NGF antagonist TrkA-Fc leads to perivascular inflammation and marked vasoconstriction. This effect is not observed with either reagent alone or in combination with other control proteins. Because NGF supports sympathetic neuron health, we tested the hypothesis that BDNF combined with sympathetic compromise caused this effect. Superior cervical ganglia were removed bilaterally with concurrent BDNF infusion into hippocampus. Perivascular inflammation was observed at 3 days, but not 12 days post treatment, when sympathetic terminals had receded, suggesting that the presence of these terminals was necessary for inflammation. Since sympathetic dysfunction may lead to compensatory overactivity of norepinephrine (NE) signaling, we co-infused BDNF with NE in the hippocampus and observed perivascular inflammation. In humans, sympathetic overactivity has been reported in a variety of vascular diseases. Some of these diseases, e.g. primary Raynaud's, are not accompanied by serious inflammatory disease whereas others, such as scleroderma and systemic lupus, are. We speculate that BDNF may contribute to the transformation of sympathetic dysfunction to inflammatory disease.

Animals↗
PubMed2006

Tlx acts as a proangiogenic switch by regulating extracellular assembly of fibronectin matrices in retinal astrocytes.

In response to hypoxia, hypoxia-inducible factors act as the primary proangiogenic triggers by regulating transcription levels of target genes, including VEGF. However, little is known about the specific factors that control other components of the angiogenic process, particularly formation of matrix scaffolds that promote adhesion and migration of endothelial cells. We show that in the postnatal mouse retina, the orphan nuclear receptor tailless (Tlx) is strongly expressed in the proangiogenic astrocytes, which secrete VEGF and fibronectin. Tlx expression by retinal astrocytes is controlled by oxygen concentration and rapidly downregulated upon contact with blood vessels. In mice null for Tlx, retinal astrocytes maintain VEGF expression; however, the extracellular assembly of fibronectin matrices by astrocytes is severely impaired, leading to defective scaffold formation and a complete failure of normal retinal vascular development. This work identifies Tlx as an essential component of the molecular network involved in the hypoxia-inducible proangiogenic switch in retinal astrocytes.

Animals↗
PubMed2006

Expression, localization and hormonal control of angiopoietin-1 in the rhesus macaque endometrium: potential role in spiral artery growth.

Angiopoietin-1 (Ang-1) is an important angiogenic factor that has not been thoroughly studied in the primate endometrium. We evaluated the endometrial expression of Ang-1 and its receptor, Tie2, during induced menstrual cycles in rhesus macaques. Tie2 expression was confined to the vascular endothelium without marked change during the cycle. However, Ang-1 expression varied considerably during the cycle. In the proliferative phase, Ang-1 was only expressed in the basal zone glands, and this expression was estradiol (E2) dependent. In the early- to mid-secretory phase, Ang-1 expression spread to the upper glands, luminal epithelium and the vascular smooth muscle cells (VSMC) of spiral arteries. In the late secretory phase, the signal disappeared from the glands but remained elevated in the VSMC of spiral arteries. Notably, there was a significant correlation between VSMC proliferation and Ang-1 expression in the VSMC of the spiral arteries. Progesterone (P) withdrawal in the early secretory phase induced a decline in Ang-1 expression in the glands and VSMC of spiral arteries along with a complete suppression of VSMC proliferation. These data suggest, for the first time, that Ang-1 may play a key role in the P-dependent growth of the unique spiral arteries in the primate endometrium.

Angiopoietin-1↗
PubMed2006

Administration of vascular endothelial growth factor Trap during the 'post-angiogenic' period of the luteal phase causes rapid functional luteolysis and selective endothelial cell death in the marmoset.

The intense angiogenesis characteristic of early corpus luteum development is dependent upon vascular endothelial growth factor (VEGF) as inhibitors of VEGF administered at the peri-ovulatory period suppress endothelial cell proliferation and progesterone secretion. We now report that administration of VEGF Trap, a soluble decoy receptor-based inhibitor, at the mid- or the late luteal phase in the marmoset results in a rapid decline in plasma progesterone. Since vascularisation of the corpus luteum is largely complete by the mid-luteal phase, it suggested that this functional luteolysis involved mechanisms other than inhibition of angiogenesis. A second experiment investigated the role of VEGF in maintaining the integrity of the luteal vasculature and hormone-producing cells. VEGF Trap was administered to marmosets in the mid-luteal phase and ovaries were obtained 1, 2, 4 or 8 days later for localisation of activated caspase-3 staining in the corpus luteum and compared with those obtained 2, 4 and 8 days after administration of control protein. The number of cells with activated caspase-3 staining was significantly increased after administration of VEGF Trap. Dual staining of activated caspase-3 with the endothelial cell marker CD31 showed that at 1 day post-treatment, more than 90% caspase-3-stained cells were vascular endothelium, prior to detection of an increasing incidence in death of hormone-producing cells on days 2 and 4. Staining with CD31 showed that the endothelial cell area was decreased after treatment. By 8 days after treatment, corpora lutea had regressed to varying degrees, while all control corpora lutea remained healthy. These results show that VEGF inhibition in the mid- or the late luteal phase induces functional luteolysis in the marmoset that is associated with premature and selective death of endothelial cells.

Angiogenesis Inhibitors↗
PubMed2005

Vascular endothelial growth factor Trap suppresses ovarian function at all stages of the luteal phase in the macaque.

CONTEXT: Fertility is dependent on a functioning corpus luteum, the formation of which is associated with intense angiogenesis. The role of angiogenic factors, such as vascular endothelial growth factor (VEGF), in luteal function has yet to be defined in primates. OBJECTIVE: The objective of this study was to determine effects of inhibiting VEGF by a VEGF Trap, a receptor-based inhibitor, administered at the early or midluteal phase, on pituitary-ovarian function. DESIGN: Effects of a single injection of VEGF Trap at three doses in the early luteal phase or a single dose in the midluteal phase were investigated and compared with control cycles. SETTING: This work was conducted in the Primate Unit. PARTICIPANTS: Eleven stump-tailed macaques with regular ovulatory cycles participated in this study. VEGF Trap was well tolerated, and all completed the study. INTERVENTIONS: A single injection of VEGF Trap at a dose of 4, 1, or 0.25 mg/kg was administered in the early luteal phase or 1 mg/kg in the midluteal phase. Controls received vehicle or the constant region of human IgG. MAIN OUTCOME MEASURES: Changes in serum concentrations of progesterone, estradiol, LH, FSH, inhibin A, VEGF Trap, and menstrual bleeding were the main outcome measures. RESULTS: Early luteal treatment caused a significant attenuation of the normal serum progesterone and estradiol concentrations, followed by a marked increase in LH and FSH. Inhibin A was not significantly reduced. After 1- and 4-mg/kg doses, progesterone remained suppressed throughout the luteal phase, and premature menstruation occurred; whereas the response to the 0.25-mg/kg dose was transitory, and menstruation was at the normal time. Midluteal treatment also resulted in a significant suppression of progesterone secretion. CONCLUSIONS: VEGF is essential for both the development and maintenance of luteal function.

Animals↗
PubMed2005

Resistance to diet-induced obesity in mice globally overexpressing OGH/GPB5.

We identified a glycoprotein hormone beta-subunit (OGH, also called GPB5) that, as a heterodimer with the alpha-subunit GPA2, serves as a second ligand for the thyroid-stimulating hormone receptor. Mice in which the OGH gene is deleted (OGH-/-) are indistinguishable from WT littermates in body weight, response to high-fat diet, metabolic parameters, body composition, and insulin tolerance. Mice engineered to transgenically globally overexpress OGH (OGH-TG) develop approximately 2-fold elevations in their basal thyroid levels and weigh slightly less than WT littermates despite increased food intake because of an increase in their metabolic rates. Moreover, when OGH-TG mice are challenged with a high-fat diet, they gain significantly less weight and body fat than their WT littermates. The OGH-TG mice also have reduced blood glucose, insulin, cholesterol, and triglycerides. In contrast to other approaches in which the thyroid axis is activated, OGH-TG mice exhibit only minor changes in heart rate and blood pressure. Our findings suggest that constitutive low-level activation of the thyroid axis (via OGH or other means) may provide a beneficial therapeutic approach for combating diet-induced obesity.

Animals↗
PubMed2005

Absence of the lipid phosphatase SHIP2 confers resistance to dietary obesity.

Genetic ablation of Inppl1, which encodes SHIP2 (SH2-domain containing inositol 5-phosphatase 2), was previously reported to induce severe insulin sensitivity, leading to early postnatal death. In the previous study, the targeting construct left the first eighteen exons encoding Inppl1 intact, generating a Inppl1(EX19-28-/-) mouse, and apparently also deleted a second gene, Phox2a. We report a new SHIP2 knockout (Inppl1(-/-)) targeted to the translation-initiating ATG, which is null for Inppl1 mRNA and protein. Inppl1(-/-) mice are viable, have normal glucose and insulin levels, and normal insulin and glucose tolerances. The Inppl1(-/-) mice are, however, highly resistant to weight gain when placed on a high-fat diet. These results suggest that inhibition of SHIP2 would be useful in the effort to ameliorate diet-induced obesity, but call into question a dominant role of SHIP2 in modulating glucose homeostasis.

Animals↗
PubMed2005

Agouti-related protein-deficient mice display an age-related lean phenotype.

Endogenous modulators of the central melanocortin system, such as the agouti-related protein (AgRP), should hold a pivotal position in the regulation of energy intake and expenditure. Despite this, AgRP-deficient mice were recently reported to exhibit normal food intake, body weight gain, and energy expenditure. Here we demonstrate that 2- to 3-month-old Agrp null mice do in fact exhibit subtle changes in response to feeding challenges (fasting and MCR agonists) but, of more significance and magnitude, exhibit reduced body weight and adiposity after 6 months of age. This age-dependent lean phenotype is correlated with increased metabolic rate, body temperature, and locomotor activity and increased circulating thyroid hormone (T4 and T3) and BAT UCP-1 expression. These results provide further proof of the importance of the AgRP neuronal system in the regulation of energy homeostasis.

Adipose Tissue↗
PubMed2004

Single injections of vascular endothelial growth factor trap block ovulation in the macaque and produce a prolonged, dose-related suppression of ovarian function.

Follicular development is associated with intense angiogenesis and increased permeability of blood vessels under the control of locally produced angiogenic factors such as vascular endothelial growth factor (VEGF). The aim of the present study was to evaluate the effects of transient inhibition of VEGF on pituitary-ovarian function in the macaque. Animals were given a single, iv injection of a potent, receptor-based VEGF antagonist, the VEGF Trap. VEGF Trap was given at a dose of 4, 1, or 0.25 mg/kg in the midfollicular phase or at 1.0 mg/kg in the late follicular phase. Controls were treated with vehicle or a control protein, recombinant human Fc (1 mg/kg). Blood samples were collected once daily for 12 d after injection, and three times per week thereafter until normal ovulatory cycles had resumed. The VEGF Trap produced a rapid suppression of estradiol and inhibin B concentrations at all doses tested, followed by a marked and sustained increase in LH and FSH. Ovulation and formation of a functional corpus luteum, as evidenced by increased serum progesterone levels, failed to occur at the anticipated time. Normal ovarian activity resumed when plasma concentrations of unbound VEGF Trap fell below about 1 mg/liter. When treatment was initiated in the midfollicular phase, control macaques ovulated 7.2 +/- 0.4 d later, but ovulation was delayed in a dose-dependent manner by VEGF Trap, occurring 23 +/- 0.7, 30 +/- 1.4, and 43 +/- 0.8 d after injection of 0.25, 1, or 4 mg/kg, respectively. Thus, the VEGF Trap exerts a potent, dose-dependent, but reversible inhibitory effect on ovarian function.

Animals↗
PubMed2004

Vascular endothelial growth factor regulates reendothelialization and neointima formation in a mouse model of arterial injury.

BACKGROUND: The rate of reendothelialization is critical in neointima formation after arterial injury. Vascular endothelial growth factor (VEGF), a potent endothelial mitogen, has been advocated for accelerating endothelial repair and preventing intimal hyperplasia after percutaneous coronary interventions. However, the precise mechanism of action of VEGF treatment and the physiologic role of endogenous VEGF after arterial injury are not well described. To better understand the role of VEGF in arterial repair, we overexpressed both VEGF and a soluble, chimeric VEGF receptor (VEGF-trap), which binds free VEGF with high affinity, in a mouse model of arterial injury. METHODS AND RESULTS: Four groups of C57BL/6 mice underwent denuding endothelial injury 1 day after systemic injection of recombinant adenovirus expressing (1) VEGF, (2) VEGF-trap, (3) VEGF plus VEGF-trap, or (4) control adenovirus. Circulating levels of adenovirus-encoded proteins were significantly elevated after gene transfer. VEGF overexpression accelerated reendothelialization and increased luminal endothelial cell proliferation 2 weeks after arterial injury (P<0.05), resulting in decreased neointima formation at 4 weeks compared with control (P<0.01). Cotreatment with VEGF-trap completely sequestered free VEGF and abrogated the beneficial effect of VEGF overexpression. Interestingly, sequestration of endogenous VEGF by VEGF-trap overexpression alone also led to delayed reendothelialization at 2 weeks (P<0.01) and increased neointima formation at 4 weeks (P<0.01). CONCLUSIONS: VEGF overexpression accelerated endothelial repair and inhibited neointima formation after arterial injury. Conversely, sequestration of exogenous and/or endogenous VEGF by VEGF-trap delayed reendothelialization and significantly increased neointima size. This demonstrates the therapeutic potential of VEGF but also emphasizes the important physiologic role of endogenous VEGF in vascular repair.

Angioplasty↗
PubMed2004

Genetic deletion of ghrelin does not decrease food intake but influences metabolic fuel preference.

Ghrelin is a recently identified growth hormone (GH) secretogogue whose administration not only induces GH release but also stimulates food intake, increases adiposity, and reduces fat utilization in mice. The effect on food intake appears to be independent of GH release and instead due to direct activation of orexigenic neurons in the arcuate nucleus of the hypothalamus. The effects of ghrelin administration on food intake have led to the suggestion that inhibitors of endogenous ghrelin could be useful in curbing appetite and combating obesity. To further study the role of endogenous ghrelin in appetite and body weight regulation, we generated ghrelin-deficient (ghrl(-/-)) mice, in which the ghrelin gene was precisely replaced with a lacZ reporter gene. ghrl(-/-) mice were viable and exhibited normal growth rates as well as normal spontaneous food intake patterns, normal basal levels of hypothalamic orexigenic and anorexigenic neuropeptides, and no impairment of reflexive hyperphagia after fasting. These results indicate that endogenous ghrelin is not an essential regulator of food intake and has, at most, a redundant role in the regulation of appetite. However, analyses of ghrl(-/-) mice demonstrate that endogenous ghrelin plays a prominent role in determining the type of metabolic substrate (i.e., fat vs. carbohydrate) that is used for maintenance of energy balance, particularly under conditions of high fat intake.

Animals↗
PubMed2004

VEGF-mediated inflammation precedes angiogenesis in adult brain.

Vascular endothelial growth factor (VEGF) has been shown to induce angiogenesis when infused continuously into adult rat brain tissue. In addition, VEGF has been shown to enhance permeability in brain vasculature. Adult rats were continuously infused with mouse VEGF into neocortex for up to 7 days. We studied the development of VEGF-induced vasculature in rat neocortex and evaluated the temporal expression of a wide variety of markers for inflammation and vascular leak in relation to the angiogenic response using immunohistochemistry and Western blot analysis. We report here that VEGF-mediated inflammation in brain is characterized by upregulation of ICAM-1 and the chemokine MIP-1alpha, as well as a preferential extravasation of monocytes. VEGF causes a dramatic breakdown of the blood-brain barrier, which is characterized by decreased investment of the vasculature with astroglial endfeet. Perivascular cells, in contrast, increase around the newly formed cerebrovasculature. In addition, breakdown of the blood-brain barrier, leukocyte extravasation, and extracellular matrix deposition occur before vascular proliferation. Furthermore, administration of low doses of VEGF induces permeability and inflammation without appreciable vascular proliferation.

Animals↗
PubMed2004

Inhibition of hemangiogenesis and lymphangiogenesis after normal-risk corneal transplantation by neutralizing VEGF promotes graft survival.

PURPOSE: To evaluate the occurrence and time course of hem- and lymphangiogenesis after normal-risk corneal transplantation in the mouse model and to test whether pharmacologic strategies inhibiting both processes improve long-term graft survival. METHODS: Normal-risk allogeneic (C57BL/6 to BALB/c) and syngeneic (BALB/c to BALB/c) corneal transplantations were performed and occurrence and time course of hem- and lymphangiogenesis after keratoplasty was observed, by using double immunofluorescence of corneal flatmounts (with CD31 as a panendothelial and LYVE-1 as a lymphatic vascular endothelium-specific marker). A molecular trap designed to eliminate VEGF-A (VEGF Trap(R1R2); 12.5 mg/kg) was tested for its ability to inhibit both processes after keratoplasty and to promote long-term graft survival (intraperitoneal injections on the day of surgery and 3, 7, and 14 days later). RESULTS: No blood or lymph vessels were detectable immediately after normal-risk transplantation in either donor or host cornea, but hem- and lymphangiogenesis were clearly visible at day 3 after transplantation. Both vessel types reached donor tissue at 1 week after allografting and similarly after syngeneic grafting. Early postoperative trapping of VEGF-A significantly reduced both hem- and lymphangiogenesis and significantly improved long-term graft survival (78% vs. 40%; P < 0.05). CONCLUSIONS: There is concurrent, VEGF-A-dependent hem- and lymphangiogenesis after normal-risk keratoplasty within the preoperatively avascular recipient bed. Inhibition of hem- and lymphangiogenesis (afferent and efferent arm of an immune response) after normal-risk corneal transplantation improves long-term graft survival, establishing early postoperative hem- and lymphangiogenesis as novel risk factors for graft rejection even in low-risk eyes.

Animals↗
PubMed2004

VEGF-A stimulates lymphangiogenesis and hemangiogenesis in inflammatory neovascularization via macrophage recruitment.

Lymphangiogenesis, an important initial step in tumor metastasis and transplant sensitization, is mediated by the action of VEGF-C and -D on VEGFR3. In contrast, VEGF-A binds VEGFR1 and VEGFR2 and is an essential hemangiogenic factor. We re-evaluated the potential role of VEGF-A in lymphangiogenesis using a novel model in which both lymphangiogenesis and hemangiogenesis are induced in the normally avascular cornea. Administration of VEGF Trap, a receptor-based fusion protein that binds and neutralizes VEGF-A but not VEGF-C or -D, completely inhibited both hemangiogenesis and the outgrowth of LYVE-1(+) lymphatic vessels following injury. Furthermore, both lymphangiogenesis and hemangiogenesis were significantly reduced in mice transgenic for VEGF-A(164/164) or VEGF-A(188/188) (each of which expresses only one of the three principle VEGF-A isoforms). Because VEGF-A is chemotactic for macrophages and we demonstrate here that macrophages in inflamed corneas release lymphangiogenic VEGF-C/VEGF-D, we evaluated the possibility that macrophage recruitment plays a role in VEGF-A-mediated lymphangiogenesis. Either systemic depletion of all bone marrow-derived cells (by irradiation) or local depletion of macrophages in the cornea (using clodronate liposomes) prior to injury significantly inhibited both hemangiogenesis and lymphangiogenesis. We conclude that VEGF-A recruitment of monocytes/macrophages plays a crucial role in inducing inflammatory neovascularization by supplying/amplifying signals essential for pathological hemangiogenesis and lymphangiogenesis.

Animals↗
PubMed2004

Ciliary neurotrophic factorAx15 alters energy homeostasis, decreases body weight, and improves metabolic control in diet-induced obese and UCP1-DTA mice.

Ciliary neurotrophic factor (CNTF) potently reduces appetite and body weight in rodents and humans. We studied the short- and long-term effects of CNTF(Ax15), a second-generation CNTF analog, in diet-induced obese C57BL/6J mice and brown adipose tissue (BAT)-deficient obese UCP1-DTA (uncoupling protein 1-diphtheria toxin A) mice. CNTF(Ax15) administration (0.1, 0.3, or 1.0 microg . g(-1) . day(-1) s.c.) for 3 or 7 days reduced food intake and body weight (mainly body fat mass). The effect of CNTF(Ax15) on food intake and body weight was more pronounced in CNTF(Ax15)-treated diet-induced obese C57BL/6J mice compared with pair-fed controls and was associated with suppressed expression of hypothalamic neuropeptide Y and agouti gene-related protein. Moreover, CNTF(Ax15) increased uncoupling protein 1 mRNA expression in BAT and energy expenditure in diet-induced obese C57BL/6J mice. Longitudinal observations revealed a sustained reduction in body weight for several days post-CNTF(Ax15) treatment of CNTF(Ax15)-treated but not pair-fed mice, followed by a gradual regain in body weight over 28 days. Finally, CNTF(Ax15) administration improved the metabolic profile in both diet-induced obese C57BL/6J and UCP1-DTA mice and resulted in a significantly improved glycemic response to oral glucose tolerance tests in CNTF(Ax15)-treated UCP1-DTA compared with pair-fed mice of similar body weight. These data suggest that CNTF(Ax15) may act through a pathway downstream of the putative point responsible for leptin resistance in diet-induced obese C57BL/6J and UCP1-DTA mice to alter food intake, body weight, body composition, and metabolism. CNTF(Ax15) has delayed and persistent effects in diet-induced obese C57BL/6J mice, which account for a reduction in body weight over and above what would be expected based on decreased foot intake alone.

Animals↗
PubMed2003

VEGF-TRAP(R1R2) suppresses choroidal neovascularization and VEGF-induced breakdown of the blood-retinal barrier.

Vascular endothelial growth factor (VEGF) plays a central role in the development of retinal neovascularization and diabetic macular edema. There is also evidence suggesting that VEGF is an important stimulator for choroidal neovascularization. In this study, we investigated the effect of a specific inhibitor of VEGF, VEGF-TRAP(R1R2), in models for these disease processes. VEGF-TRAP(R1R2) is a fusion protein, which combines ligand binding elements taken from the extracellular domains of VEGF receptors 1 and 2 fused to the Fc portion of IgG1. Subcutaneous injections or a single intravitreous injection of VEGF-TRAP(R1R2) strongly suppressed choroidal neovascularization in mice with laser-induced rupture of Bruch's membrane. Subcutaneous injection of VEGF-TRAP(R1R2) also significantly inhibited subretinal neovascularization in transgenic mice that express VEGF in photoreceptors. In two models of VEGF-induced breakdown of the blood-retinal barrier (BRB), one in which recombinant VEGF is injected into the vitreous cavity and one in which VEGF expression is induced in the retina in transgenic mice, VEGF-TRAP(R1R2) significantly reduced breakdown of the BRB. These data confirm that VEGF is a critical stimulus for the development of choroidal neovascularization and indicate that VEGF-TRAP(R1R2) may provide a new agent for consideration for treatment of patients with choroidal neovascularization and diabetic macular edema.

Animals↗
PubMed2003

VEGF-dependent conjunctivalization of the corneal surface.

PURPOSE: To investigate the mechanisms governing corneal neovascularization and the appearance of goblet cells in a murine model of limbal insufficiency. METHODS: The spatial and time-dependent relationship between corneal neovascularization and goblet cell density was analyzed in corneal flatmounts. Immunohistochemical detection of the vascular endothelial growth factor (VEGF) receptor Flt-1 (VEGFR1) was performed in paraffin-embedded sections. A transgenic mouse that expresses the reporter gene lacZ targeted to the Flt-1 locus through homologous recombination was used to analyze corneal expression of Flt-1. The presence of soluble and membranous goblet cell Flt-1 mRNA and protein content was assessed with Northern and Western blot analyses, respectively. Finally, systemic adenoviral expression of a soluble Flt-1/Fc construct was used to study the effect of inhibition of VEGF bioactivity on the appearance of goblet cells and neovascularization. RESULTS: Corneal neovascularization preceded the appearance of goblet cells, although both processes overlapped temporally. Flt-1 was abundant in the conjunctiva-like epithelium covering the cornea, as well as in the goblet cells, invading leukocytes, and vasculature. A similar expression pattern was observed in the transgenic mice expressing the lacZ gene downstream from the Flt-1 promoter. Isolated human and rat goblet cells in culture expressed Flt-1 mRNA and protein, as did freshly isolated human conjunctiva. The systemic inhibition of VEGF bioactivity potently suppressed both corneal neovascularization (8.3% +/- 8.1% vs. 41.1% +/- 15.3% corneal area; P < 0.001) and corneal goblet cell density (1.6% +/- 2.5% vs. 12.2% +/- 2.4% corneal area; P < 0.001). CONCLUSIONS: Two important features of corneal conjunctivalization, the appearance of goblet cells and neovascularization, are regulated by VEGF. Both processes are probably mediated, in part, through the Flt-1 receptor. Taken together, these data indicate that an anti-VEGF therapeutic approach may limit the visual loss associated with conjunctivalization of the corneal surface.

Animals↗