Watching lymphatic vessels grow by making them glow

Proulx, Steven T.; Detmar, Michael

doi:10.1038/cr.2011.191

Cited by 4 publications

(2 citation statements)

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“…In vitro , podoplanin increased tumor cell motility as well as lymphatic endothelial cell (LEC) migration and tubulogenesis. Podoplanin upregulation may be induced by increased lymph flow to the draining lymph nodes, which occurs in lymphangiogenic tumors unless metastasis is extensive enough to be obstructive (24). Interestingly, both increased lymph flow from the tumor as well as lymph node metastasis appear to depend on tumor-draining lymph node lymphangiogenesis, according to new evidence presented by Alanna Ruddell (Fred Hutchison Cancer Research Center, Seattle, WA).…”

Section: Introductionmentioning

confidence: 99%

Tumor Microenvironment Complexity: Emerging Roles in Cancer Therapy

et al. 2012

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The tumor microenvironment (TME) consists of cells, soluble factors, signaling molecules, extracellular matrix, and mechanical cues that can promote neoplastic transformation, support tumor growth and invasion, protect the tumor from host immunity, foster therapeutic resistance, and provide niches for dormant metastases to thrive. An American Association for Cancer Research (AACR) special conference held on November 3–6, 2011, addressed five emerging concepts in our understanding of the TME: its dynamic evolution, how it is educated by tumor cells, pathways of communication between stromal and tumor cells, immunomodulatory roles of the lymphatic system, and contribution of the intestinal microbiota. These discussions raised critical questions on how to include the analysis of the TME in personalized cancer diagnosis and treatment.

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Section: Introductionmentioning

confidence: 99%

Tumor Microenvironment Complexity: Emerging Roles in Cancer Therapy

et al. 2012

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“…Indeed, several groups still refer to lymphatic contractile behavior in the mouse as passive ‘pulses’ rather than active ‘contractions’ presumably due to an inability to measure vessel diameter accurately (Kwon & Sevick‐Muraca, 2010; Zhou et al . 2010; Proulx & Detmar, 2012). Notably, only a single, recent study has demonstrated the possible existence of large‐amplitude contractions of mouse collecting lymphatics in vivo (Liao et al .…”

Section: Introductionmentioning

confidence: 99%

Genetic removal of basal nitric oxide enhances contractile activity in isolated murine collecting lymphatic vessels

Scallan

Davis

2013

The Journal of Physiology

106

129

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Key points• Stimulation of nitric oxide (NO) production by lymphatic endothelium was originally thought to inhibit lymphatic contractile function.• However, recent studies have suggested that basal NO paradoxically increases the strength of contractions as a consequence of decreasing contraction frequency.• Here, we tested that hypothesis directly for the first time by establishing a new preparation where lymphatic vessels were isolated from transgenic mice and retained robust contractile activity.• Genetic removal of basal NO using endothelial NO synthase −/− mice led to an increase in contraction strength without increasing contraction frequency, opposing this hypothesis. In contrast, higher levels of NO production stimulated by ACh inhibited lymphatic contractile function in wild-type and inducible NO synthase −/− mice, consistent with previous studies.• Our results show that NO functions in the peripheral lymphatic vasculature to depress contractile function, which will ultimately depress lymph flow that determines fluid homeostasis, humoral immunity and cancer metastasis.Abstract The role of nitric oxide (NO) in regulating lymphatic contractile function and, consequently, lymph flow has been the subject of intense study. Despite this, the precise effects of NO on lymphatic contractile activity remain unclear. Recent hypotheses posit that basal levels of endogenous NO increase lymphatic contraction strength as a consequence of lowering frequency (i.e. positive lusitropy), whereas higher agonist-evoked concentrations of NO exert purely inhibitory effects on contractile function. We tested both hypotheses directly by isolating and cannulating collecting lymphatic vessels from genetically modified mice for ex vivo study. The effects of basal NO and agonist-evoked NO were evaluated, respectively, by exposing wild-type (WT), endothelial NO synthase (eNOS) −/− and inducible NO synthase (iNOS) −/− lymphatic vessels to controlled pressure steps followed by ACh doses. To compare with pharmacological inhibition of eNOS, we repeated both tests in the presence of L-NAME. Surprisingly, genetic removal of basal NO enhanced contraction amplitude significantly without increasing contraction frequency. Higher levels of NO production stimulated by ACh evoked dilation, decreased tone, slowed contraction frequency and reduced fractional pump flow. We conclude that basal NO specifically depresses contraction amplitude, and that greater NO production then inhibits all other aspects of contractile function. Further, this work demonstrates definitively that mouse collecting lymphatic vessels exhibit autonomous, large-amplitude contractions that respond to pressure similarly to collecting lymphatics of other mammalian species. At least in the peripheral

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