Cell autonomous role of lymphatic VEGFR2 signaling in diet induced obesity
Developmental Biology
Final Report Abstract
The hosting laboratories data published in Science showed that increased VEGFA levels in Nrp1,Flt1iEKO mice caused the lacteal junction zippering and prevented lipid uptake. The main receptor activated by VEGFA is VEGFR2. However, VEGFR2 is expressed by both BECs and LECs within intestinal villi 15-16. Therefore, it remains possible that the lacteal junction zippering is a secondary effect of VEGFR2 signaling in BECs. To identify if VEGFR2 activation in LEC is directly controlling junction zippering, this project aimed to determine LEC-autonomous effects of VEGFR2 on lacteal junctions, using LEC-specific genetic VEGFR2 loss of function (Aim 1.1) and gain of function (Aim 1.2) models. In addition, I plan to explore the possibility of targeting VEGFR signaling via protein tyrosine phosphatases (PTPs). LEC specific PTPN1 loss of function experiments were performed. The experiments were performed as described in the suggested research plan increased the knowledge about lymphatic cell autonomous VEGFR2 signaling. The VEGFR2 loss of function experiments showed that lymphatic specific loss of VEGFR2 results in initial lymphatics that do not change their button to zipper junction in response to VEGFA treatment. The lymphatic specific gain of function experiments further supported that finding. The lacteals that express the constitutive active form of VEGFR2 (TdTomato positive) showed an increase in zipper junctions. The PTPN1 loss of function experiments did not show changes in initial lymphatic junctions but the mice gain more body weight, indicating potential phenotypes in collecting lymphatic vessels that were not further investigated. The obtained results for the VEGFR2 gain and loss of function experiments increased our knowledge about cell autonomous VEGFR2 signaling in initial lymphatics.
