Page 11 - Y. Vascular biology

Y-7 PLVAP is essential for the maturation and maintenance of
choroidal blood vessels
,
, ,*
SOO JIN KIM¹³, SANG A. KIM³, YEONG A. CHOI³, YURIM KIM³, YOSHIAKI KUBOTA⁴, GOU YOUNG KOH⁵, DO YOUNG PARK³, JUNYEOP LEE¹ ²
¹Asan Institute for Life Science, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea, ²Departement of Ophthalmology, Asan Medical Center, University of Ulsan
College of Medicine, Seoul 05505, Korea, ³Departement of Ophthalmology, Yeungnam University College of Medicine, Daegu 42415, Korea, ⁴Department of Anatomy, Keio University School
of Medicine, Tokyo 160-8582, Japan, ⁵Center for Vascular Research, Institute for Basic Science (IBS), Daejeon 34126, Korea
BACKGROUND AIM
Endothelial fenestration is a transvascular channel for We investigated the role of PLVAP in maturation and
exchanging nutrients and metabolites. Plasmalemmal vesicle- maintenance of choroid vascular system for the first time.
associated protein (PLVAP) forms fenestration and its
diaphragm.
METHODS
We used tamoxifen-inducible endothelial cell-specific PLVAP conditional knockout mice(VE-cadherin-Cre-ERT2: PLVAPflox/flox;
PLVAP-ECKO, KO) in C57BL/6 background. We deleted PLVAP at P1-5 during maturation or deleted it at adult to evaluate the
stability and maintenance. We also re-expressed PLVAP in PLVAP-ECKO as a rescue by PLVAP plasmid transfection. We used
ultra-widefield (UWF) angiography and optical coherence tomography (OCT), electron microscopy as well as immunostaining and
molecular analysis. Human choroids were harvested from donor eyes.
RESULTS
In Human, Aging and DR, an representative example of vision threatening ocular vascular disease, reduces PLVAP expression
and disorients Fenestrations. (Fig 1) Vascular endothelial cell specific conditional deletion of PLVAP shows reduced
fenestrations but increased in disoriented fenestration ratio, dilated choroid vessels with leakage, disrupted RPE and
photoreceptor layers, which, in result, reduced visual function. (Fig 2) Vascular smooth muscle cells(VSMC) and pericytes were
significantly lost with reduced PDGFB expression level. VEGFA and VEGFR2 levels were also reduced. Non-diaphragmed
fenestrations and caveolae were significantly increased at choriocapillaris. (Fig 3) PLVAP ECKO also induced RPE
degeneration. Number of Macrophages were notably increased and migrated toward choriocapillaris from the choroid stroma-
sclera layer. Activated microglial cells were recruited toward choroid large vessel layer. (Fig 4) PLVAP ECKO in postmature
show severe RPE degeneration and photoreceptor degeneration. Retinal was thinned, but choroid was thickened with large
vessel dilation and leakage. (Fig 5) As we rescued PLVAP to PLVAP-ECKO, the number of fenestrations and diaphragms were
restored, and the leakage at choroidal was also reduced. (Fig 6)

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