Thursday, July 17, 2025 7/17/2025

VEGFR Signaling Controls Lymphatic Junctions

Award Number: R01HL164825
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2022
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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VEGFR Signaling Controls Lymphatic Junctions - Congenital lymphedema is caused by inherited gene mutations that impair the functioning of the lymphatic vasculature and lead to swelling of the limbs, disfigurement, cellulitis, and increased susceptibility to MRSA infections of the skin and sepsis. Congenital lymphedema is also a comorbidity of lymphatic malformations and other common syndromes (e.g. Noonan). The most common gene mutation that causes congenital lymphedema is a heterozygous inactivating mutation in the VEGFR3 gene that causes Milroy’s disease. While VEGFR3 has been widely studied as the main receptor that induces lymphangiogenesis, virtually nothing is known about how VEGFR3 regulates physiological functions of the lymphatic vasculature. Thus, the pathogenesis of Milroy’s disease remains unknown, prohibiting the development of drug therapies. Patients with congenital mutations in VEGFR3 have lower leg lymphedema and upon lymphoscintigraphy imaging it is revealed that their lymphatic vessels are unable to absorb any tracer from the interstitium. Here, we have developed a mouse model in which the VEGFR3 gene can be deleted specifically from the lymphatic vasculature to understand its physiological functions. Our preliminary data show that loss of VEGFR3 negatively affects the ability of lymphatic capillaries to remodel their continuous cell-cell junctions, reminiscent of zippers, into discontinuous wide-open junctions called buttons. Junctional remodeling in the lymphatic capillaries is a relatively new biological process that is poorly understood but relies on the adherens junction protein, VE-cadherin, in which our laboratory has expertise. Importantly, the button junctions are thought to enable fluid absorption from the interstitium. Our preliminary data identify VEGFR3 as a novel regulator of lymphatic capillary junction remodeling to form button junctions. We will combine this mouse model with cell culture and physiological approaches to investigate the role of VEGFR3 in the lymphatic vasculature in the following specific aims. In Aim 1, we will assess the ability of lymphatic capillaries to remodel their junctions in the absence of VEGFR3 at various timepoints after birth. We will also investigate whether VEGFR3 is required not only for button junction formation, but also for the lifelong maintenance of these special junctions. Lymph flow will be assessed in vivo to determine how the loss of button junctions affects physiological interstitial fluid absorption. In Aim 2, we will investigate the downstream cell signals that regulate button junction formation and identify the signaling pathways involved using a variety of approaches. The completion of these aims will identify a new signaling pathway by which VEGFR3 controls lymphatic junction remodeling to enable interstitial fluid absorption by the lymphatic capillaries. This work will significantly impact patients with congenital lymphedema by providing mechanistic insight into the pathogenesis of the disease, opening the door to developing pharmacological treatments.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $663,120 )
2025	2025	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Cardiovascular Diseases Research	000	4	6/23/2025	NON-COMPETING CONTINUATION	$663,120
														Subtotal = $663,120

Issue Date FY: 2024 ( Subtotal = $649,857 )
2024	2024	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Cardiovascular Diseases Research	000	3	6/17/2024	NON-COMPETING CONTINUATION	$649,857
														Subtotal = $649,857

Issue Date FY: 2023 ( Subtotal = $663,120 )
2023	2023	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Cardiovascular Diseases Research	000	2	7/11/2023	NON-COMPETING CONTINUATION	$663,120
														Subtotal = $663,120

Issue Date FY: 2022 ( Subtotal = $660,910 )
2022	2022	UNIVERSITY OF SOUTH FLORIDA	4202 E FOWLER AVE	TAMPA	FL	33620	HILLSBOROUGH	USA	Cardiovascular Diseases Research	000	1	6/10/2022	NEW	$660,910
														Subtotal = $660,910

Grand Total All Awards = $2,637,007

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VEGFR Signaling Controls Lymphatic Junctions

Award Number: R01HL164825

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/01/2022

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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