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Background: Lymphangiogenesis is believed to be a protective response in the setting of multiple forms of kidney injury and mitigates the progression of interstitial fibrosis. To augment this protective response, promoting kidney lymphangiogenesis is being investigated as a potential treatment to slow the progression of kidney disease. As injury-related lymphangiogenesis is driven by signaling from the receptor VEGFR3 (vascular endothelial growth factor receptor 3) in response to the cognate growth factor VEGF (vascular endothelial growth factor)-C released by tubular epithelial cells, this signaling pathway is a candidate for future kidney therapeutics. However, the consequences to kidney development and function to targeting this signaling pathway remain poorly defined., Methods: We generated a new mouse model expressing Vegfc under regulation of the nephron progenitor Six2Cre driver strain ( Six2Vegfc ). Mice underwent a detailed phenotypic evaluation. Whole kidneys were processed for histology and 3-dimensional imaging., Results: Six2Vegfc mice had reduced body weight and kidney function compared with littermate controls. Six2Vegfc kidneys demonstrated large peripelvic fluid-filled lesions with distortion of the pelvicalcyceal system which progressed in severity with age. Three-dimensional imaging showed a 3-fold increase in total cortical vascular density. Histology confirmed a substantial increase in LYVE1+ (lymphatic vessel endothelial hyaluronan receptor-1)/PDPN+ (podoplanin)/VEGFR3+ lymphatic capillaries extending alongside EMCN+ (endomucin) peritubular capillaries. There was no change in EMCN+ peritubular capillary density., Conclusions: Kidney lymphatic density was robustly increased in the Six2Vegfc mice. There were no changes in peritubular blood capillary density despite these endothelial cells also expressing VEGFR3. The model resulted in malformation of the lymphatic hilar plexus, resulting in severe hydronephrosis that resembled a human condition termed renal lymphangiectasia. This study defines the vascular consequences of augmenting VEGFC signaling during kidney development and provides new insight into human renal lymphatic malformations., Competing Interests: S.E. Quaggin holds patents related to therapeutic targeting of the ANGPT-TEK (angiopoeitin-TEK receptor tyrosine kinase or Tie2) pathway in ocular hypertension and glaucoma and vascular diseases and owns stock in Mannin Research. S.E. Quaggin also receives consulting fees from AstraZeneca, Janssen, the Lowy Medical Research Foundation, Novartis, Pfizer, Janssen, Unity Biotechnology, and Roche/Genentech. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The other authors report no conflicts.

Kaposiform lymphangiomatosis (KLA) is a vascular anomaly featuring lymphatic expansion. It has no known cause, no effective treatment, and is associated with high morbidity. Proliferative cells from 3 KLA patient lesions were characterized relative to adiopose-derived mesenchyme stem cells (ADSCs) and cells derived from a patient with the related disease kaposiform hemangioendothelioma (KHE). KLA cells variably expressed markers of mesenchyme stem cells (CD73, CD90, CD105, CD146) and lacked endothelial cell markers (CD31, CD34) as determined by flow cytometry. They expressed markers of vascular pericytes (neural/glial antigen 2, alpha-smooth muscle actin, platelet-derived growth factor-beta receptor, and CXCL12) as determined by quantitative reverse transcription polymerase chain reaction. Lesion cells transcribed vascular markers VEGFC and VEGFD, as well as VCAM-1, the latter of which was confirmed by flow cytometry, consistent with angiogenic MSC-like pericytes. Furthermore, conditioned medium from each was shown to promote the proliferation of growth factor-starved lymphatic endothelial cells. Unlike kaposiform hemangioendothelioma-derived MSC-like pericytes and ADSCs, KLA isolates were defective in support of vascular network formation in co-cultures with either vascular or lymphatic endothelial cells. Genetic analysis by whole exome sequencing revealed novel variant alleles in 2 populations of KLA cells (BAD, TSC1) that may bear on aberrant pericyte growth and function.

Purpose: To report a novel intervention for the treatment of conjunctival lymphangiectasia-subconjunctival injection of bevacizumab., Methods: A 53-year-old white male presented with a 3-month history of right ocular discomfort and redness unresponsive to conventional topical treatment of lubricants and steroids. A clinical diagnosis of conjunctival lymphangiectasia was confirmed by biopsy. Bevacizumab (25 mg/mL) was injected subconjunctivally into the affected area., Results: An improvement in the degree of conjunctival chemosis was evident at 5 days postinjection. At 1-month follow-up, symptoms had fully resolved. No recurrence had been observed at 3 years' follow-up., Conclusions: Subconjunctival bevacizumab injection may be an effective treatment for conjunctival lymphangiectasia.

Rationale: Lymphatic vessels in the respiratory tract normally mature into a functional network during the neonatal period, but under some pathological conditions they 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 (vascular endothelial growth factor-C [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 Clara cell secretory protein-reverse tetracycline-controlled transactivator/tetracycline operator-VEGF-C double-transgenic mice during a critical period from embryonic day 15.5 to postnatal day 14 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 morphological features similar to pulmonary lymphangiectasia in humans. The condition was milder in mice given doxycycline after age postnatal day 14 and did not develop after postnatal day 35. Mechanistic studies revealed that VEGF recptor (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.

Aims: To present the clinico-pathological findings of eight cases of acquired vulval lymphangiectasia (AVL) with discussion of the terminology and differential diagnosis., Methods: Vulvectomy or biopsy specimens from eight patients with AVL were reviewed. All patients had undergone surgery, lymphadenectomy and/or radiotherapy, most commonly for carcinoma of the cervix, up to 26 years prior to presentation with the lymphangiectatic lesions. Immunohistochemistry for CD31, CD34, D2-40, p53 and p16 was performed in each case., Results: The original clinical and pathological diagnoses were most frequently 'lymphangioma circumscriptum' but viral infection was considered in some cases. All specimens showed dermal lymphangiectasia associated with marked reactive epidermal hyperplasia. The lymphatic endothelial cells showed CD31 and D2-40 expression but CD34 was negative. The keratinocytes showed focal p53 immunoreactivity in four cases., Conclusions: AVL is the preferred nomenclature for the lesions presented herein. The clinical and histological features usually are characteristic but the differential diagnosis may include condyloma and differentiated type vulval intraepithelial neoplasia (VIN). Immunohistochemistry may be helpful but lack of CD34 expression should be noted and may prove useful in the differential diagnosis of other vulval vascular lesions. Focal p53 protein immunoreactivity should not be considered indicative of differentiated type VIN in this clinical setting.