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Related Concept Videos

Development of the Lymphatic System01:15

Development of the Lymphatic System

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The development of lymphatic tissues and vessels in embryonic life begins around the fifth week. These structures originate from the mesoderm layer, with lymph sacs emerging from developing veins.
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The Ras Gene02:38

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The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
Ras is a...
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Ras and Rho are small monomeric GTPases that act downstream of receptor tyrosine kinase (RTK) and regulate various cellular processes. These GTPases switch between active and inactive states by binding to guanine nucleotides.
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Matrix metalloproteases (MMPs) are enzymes involved in the hydrolysis of proteins and glycoproteins of the extracellular matrix. MMPs are essential for the migration and proliferation of cells through the dense matrix network, throughout embryonic development, and throughout morphogenesis. The first MMP activity discovered was a collagenase in a tadpole's tail undergoing metamorphosis. The active collagen deposition and modifications lead to the morphogenesis of tadpoles into the adult...
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Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
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Updated: Mar 27, 2026

Isolation of Human Lymphatic Endothelial Cells by Multi-parameter Fluorescence-activated Cell Sorting
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Lymphatic Malformations With Activating KRAS Mutations Impair Lymphatic Valve Development Through Matrix

Diandra M Mastrogiacomo1, Abbigail Price1, Yuting Fu1

  • 1Department of Molecular Pharmacology and Physiology, University of South Florida, Tampa (D.M.M., A.P., Y.F., R.B., L.A.K., K.L., Y.Y., G.E.D., J.P.S.).

Arteriosclerosis, Thrombosis, and Vascular Biology
|March 26, 2026
PubMed
Summary

Activating KRAS mutations cause lymphatic valve loss by upregulating matrix metalloproteinases (MMPs) that degrade the valve's extracellular matrix. Inhibiting MMPs rescues lymphatic valve development, revealing a key mechanism in lymphatic malformations.

Keywords:
endothelial cellslymphatic vesselsmitral valveprevalencesubclavian vein

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Last Updated: Mar 27, 2026

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Area of Science:

  • Vascular biology
  • Molecular mechanisms of disease
  • Lymphatic system development

Background:

  • Lymphatic malformations result from genetic mutations affecting lymphatic vasculature.
  • Activating KRAS mutations are linked to lymphatic malformations and associated conditions like lymphedema and chylothorax.
  • The precise mechanisms causing lymphatic valve loss in these conditions remain unclear.

Purpose of the Study:

  • To elucidate the molecular mechanisms underlying lymphatic valve loss in the context of KRAS mutations.
  • To investigate the role of specific signaling pathways and enzymes in lymphatic valve development and degradation.

Main Methods:

  • Utilized a mouse model with lymphatic-specific, inducible KRAS-G12D expression and a Prox1GFP reporter.
  • Analyzed human dermal lymphatic endothelial cells (HDLECs) with KRAS-G12D expression using qPCR, Western blot, and gel zymography.
  • Performed mechanistic studies in 3D collagen matrices and tested MMP inhibitors in vivo.

Main Results:

  • Lymphatic-specific KRAS-G12D expression attenuated lymphatic valve development in mice.
  • KRAS-G12D induced upregulation of the plasminogen activator (PA) pathway and matrix metalloproteinases (MMPs) in HDLECs.
  • MMPs, activated by plasmin, degraded the extracellular matrix (ECM) core of lymphatic valves, and MMP inhibition rescued valve formation.

Conclusions:

  • Hyperactive KRAS signaling promotes lymphatic valve loss through MMP-mediated ECM degradation.
  • The PA pathway plays a crucial role in activating MMPs involved in valve development.
  • Targeting MMPs represents a potential therapeutic strategy for lymphatic malformations.