Lymphatic Endothelial Heparan Sulfate Deficiency Results in Altered Growth Responses to Vascular Endothelial Growth Factor-C (VEGF-C)

Yin, Xin; Johns, Scott C.; Lawrence, Roger; Xu, Ding; Reddi, Krisanavane; Bishop, Joseph R.; Varner, Judith A.; Fuster, Mark M.

doi:10.1074/jbc.m110.206664

Cited by 20 publications

(13 citation statements)

References 32 publications

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“…However, interaction with heparin can influence the pattern of VEGF-C-induced lymphangiogenesis 63 . Fully processed VEGF-C can bind heparan sulfate 64 , but the extent of binding of longer forms of VEGF-C has not been determined. Further work is needed to understand the links between proteolytic processing of VEGF-C, binding to extracellular matrix, and development of lymphangiectasia.…”

Section: Discussionmentioning

confidence: 99%

Pulmonary Lymphangiectasia Resulting From Vascular Endothelial Growth Factor-C Overexpression During a Critical Period

Yao

Testini

Tvorogov

et al. 2014

Circulation Research

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Rationale: Lymphatic vessels in the respiratory tract normally mature into a functional network during the neonatal period, but under some pathological conditions can grow as enlarged, dilated sacs that result in the potentially lethal condition of pulmonary lymphangiectasia. Objective: We sought to determine whether overexpression of the lymphangiogenic growth factor VEGF-C can promote lymphatic growth and maturation in the respiratory tract. Unexpectedly, perinatal overexpression of VEGF-C in the respiratory epithelium led to a condition resembling human pulmonary lymphangiectasia, a life-threatening disorder of the newborn characterized by respiratory distress and the presence of widely dilated lymphatics. Methods and Results: Administration of doxycycline to CCSP-rtTA/tetO-VEGF-C double transgenic mice during a critical period from E15.5 to P14 was accompanied by respiratory distress, chylothorax, pulmonary lymphangiectasia, and high mortality. Enlarged sac-like lymphatics were abundant near major airways, pulmonary vessels, and visceral pleura. Side-by-side comparison revealed morphologic features similar to pulmonary lymphangiectasia in humans. The condition was milder in mice given doxycycline after age P14 and did not develop after P35. Mechanistic studies revealed that VEGFR-3 alone drove lymphatic growth in adult mice, but both VEGFR-2 and VEGFR-3 were required for the development of lymphangiectasia in neonates. VEGFR-2/VEGFR-3 heterodimers were more abundant in the dilated lymphatics, consistent with the involvement of both receptors. Despite the dependence of lymphangiectasia on VEGFR-2 and VEGFR-3, the condition was not reversed by blocking both receptors together or by withdrawing VEGF-C. Conclusions: The findings indicate that VEGF-C overexpression can induce pulmonary lymphangiectasia during a critical period in perinatal development.

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Section: Discussionmentioning

confidence: 99%

Pulmonary Lymphangiectasia Resulting From Vascular Endothelial Growth Factor-C Overexpression During a Critical Period

Yao

Testini

Tvorogov

et al. 2014

Circulation Research

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“…VEGF has been shown to significantly increase proliferation of several endothelial cell types (1,4,29). When incorporated into biomimetic hydrogels, it was observed that cell proliferation can be modulated due to the presentation of VEGF.…”

Section: Cell Proliferation: Assessment Of Erk Expression and Activationmentioning

confidence: 97%

Covalently grafted VEGF₁₆₅ in hydrogel models upregulates the cellular pathways associated with angiogenesis

Porter

Klinge²,

Gobin

2011

American Journal of Physiology-Cell Physiology

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Angiogenesis is an important biological response known to be involved in many physiological and pathophysiological situations. Cellular responses involved in the formation of new blood vessels, such as increases in endothelial cell proliferation, cell migration, and the survival of apoptosis-inducing events, have been associated with vascular endothelial growth factor isoform 165 (VEGF(165)). Current research in the areas of bioengineering and biomedical science has focused on developing polyethylene glycol (PEG)-based systems capable of initiating and sustaining angiogenesis in vitro. However, a thorough understanding of how endothelial cells respond at the molecular level to VEGF(165) incorporated into these systems has not yet been established in the literature. The goal of the current study was to compare the upregulation of key intracellular proteins involved in angiogenesis in human umbilical vein endothelial cells (HUVEC) and human microvascular endothelial cells (HMEC) seeded on PEG hydrogels containing grafted VEGF(165) and adhesion peptides Arg-Gly-Asp-Ser (RGDS). Our data suggest that the covalent incorporation of VEGF(165) into PEG hydrogels encourages the upregulation of signaling proteins responsible for increases in endothelial cell proliferation, cell migration, and the survival after apoptosis-inducing events.

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“…The N terminus of CCBE1 interacts also with VEGFR3 and the pericellular matrix components vitronectin and collagens I, IV, and V (Bos et al 2011;Jeltsch et al 2014). Immature VEGF-C also binds VEGFR3 and cell surface/ECM heparan sulfates in vitro (Yin et al 2011;Jeltsch et al 2014;Johns et al 2016). Most VEGF-C activation may thus occur on the endothelial cell surface or in the pericellular matrix.…”

Section: Vegf-c Activationmentioning

confidence: 99%

Lymphangiogenesis guidance by paracrine and pericellular factors

et al. 2017

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Lymphatic vessels are important for tissue fluid homeostasis, lipid absorption, and immune cell trafficking and are involved in the pathogenesis of several human diseases. The mechanisms by which the lymphatic vasculature network is formed, remodeled, and adapted to physiological and pathological challenges are controlled by an intricate balance of growth factor and biomechanical cues. These transduce signals for the readjustment of gene expression and lymphatic endothelial migration, proliferation, and differentiation. In this review, we describe several of these cues and how they are integrated for the generation of functional lymphatic vessel networks.

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Lymphatic Endothelial Heparan Sulfate Deficiency Results in Altered Growth Responses to Vascular Endothelial Growth Factor-C (VEGF-C)

Cited by 20 publications

References 32 publications

Pulmonary Lymphangiectasia Resulting From Vascular Endothelial Growth Factor-C Overexpression During a Critical Period

Pulmonary Lymphangiectasia Resulting From Vascular Endothelial Growth Factor-C Overexpression During a Critical Period

Covalently grafted VEGF₁₆₅ in hydrogel models upregulates the cellular pathways associated with angiogenesis

Lymphangiogenesis guidance by paracrine and pericellular factors

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Lymphatic Endothelial Heparan Sulfate Deficiency Results in Altered Growth Responses to Vascular Endothelial Growth Factor-C (VEGF-C)

Cited by 20 publications

References 32 publications

Pulmonary Lymphangiectasia Resulting From Vascular Endothelial Growth Factor-C Overexpression During a Critical Period

Pulmonary Lymphangiectasia Resulting From Vascular Endothelial Growth Factor-C Overexpression During a Critical Period

Covalently grafted VEGF165 in hydrogel models upregulates the cellular pathways associated with angiogenesis

Lymphangiogenesis guidance by paracrine and pericellular factors

Contact Info

Product

Resources

About

Covalently grafted VEGF₁₆₅ in hydrogel models upregulates the cellular pathways associated with angiogenesis