Ascending Vasa Recta Are Angiopoietin/Tie2-Dependent Lymphatic-Like Vessels

Abstract

Urinary concentrating ability is central to mammalian water balance and depends on a medullary osmotic gradient generated by a countercurrent multiplication mechanism. Medullary hyperosmolarity is protected from washout by countercurrent exchange and efficient removal of interstitial fluid resorbed from the loop of Henle and collecting ducts. In most tissues, lymphatic vessels drain excess interstitial fluid back to the venous circulation. However, the renal medulla is devoid of classic lymphatics. Studies have suggested that the fenestrated ascending vasa recta (AVRs) drain the interstitial fluid in this location, but this function has not been conclusively shown. We report that late gestational deletion of the angiopoietin receptor endothelial tyrosine kinase 2 (Tie2) or both angiopoietin-1 and angiopoietin-2 prevents AVR formation in mice. The absence of AVR associated with rapid accumulation of fluid and cysts in the medullary interstitium, loss of medullary vascular bundles, and decreased urine concentrating ability. In transgenic reporter mice with normal angiopoietin-Tie2 signaling, medullary AVR exhibited an unusual hybrid endothelial phenotype, expressing lymphatic markers (prospero homeobox protein 1 and vascular endothelial growth factor receptor 3) as well as blood endothelial markers (CD34, endomucin, platelet endothelial cell adhesion molecule 1, and plasmalemmal vesicle-associated protein). Taken together, our data redefine the AVRs as Tie2 signaling-dependent specialized hybrid vessels and provide genetic evidence of the critical role of AVR in the countercurrent exchange mechanism and the structural integrity of the renal medulla.

Lymphatic Programing and Specialization in Hybrid Vessels

“…Consequently, absence of VEGFR2 in these vessels could lead to increased VEGFR3 homo-dimer signaling (Dixelius et al, 2003). As postulated by Kenig-Kozlovsky et al (2018) VEGFR3 may be implicated in vessel widening of the AVR, which is significantly wider than the DVR, as VEGFR3 responds to fluid shear stress by promoting outward vessel remodeling (Baeyens et al, 2015).…”

“…Similar to SC, the AVR expresses both PROX1 and VEGFR3, but not LYVE1 and PDPN. Additionally, the AVR expresses endomucin and blood endothelial markers CD31, CD34, VEGFR1, and PLVAP (Table 1; Kenig-Kozlovsky et al, 2018). Interestingly, despite typically being expressed in blood vessels, VEGFR2 expression was not found in the AVR (Kenig-Kozlovsky et al, 2018).…”

“…Additionally, the AVR expresses endomucin and blood endothelial markers CD31, CD34, VEGFR1, and PLVAP (Table 1; Kenig-Kozlovsky et al, 2018). Interestingly, despite typically being expressed in blood vessels, VEGFR2 expression was not found in the AVR (Kenig-Kozlovsky et al, 2018). VEGFR2 and VEGFR3 are able to hetero-dimerize and activate downstream signaling pathways, such as AKT signaling, that differ from those triggered by homodimerized VEGFR3, such as ERK signaling (Deng et al, 2015).…”

“…As such, a growing number of endothelial lined vessels which do not fit neatly into a classical vessel type have been identified. Recently, three different vessels, termed hybrid vessels, have been found to possess a combination of blood and lymphatics markers, presumably necessary for their highly specialized function: the Schlemm's canal (SC) of the eye, the ascending vasa recta (AVR) of the renal medulla, and the remodeled spiral arteries (rSA) of the placental decidua (Aspelund et al, 2014;Park et al, 2014;Truong et al, 2014;Kenig-Kozlovsky et al, 2018;Pawlak et al, 2019). These vessels are in addition to an existing small catalog of highly specialized non-lymphatic vessels with similarly distinct expression patterns, including the liver sinusoid and high endothelial venules (HEV) of secondary lymphoid organs.…”

Role of the renin–angiotensin system in kidney development and programming of adult blood pressure

“…Deletion of the Angpt1 allele on E10.5 results in embryonic lethality with severe damages in glomerular microvascular beds, dilated capillary loops and disrupted glomerular basement membrane [120]. Using either Angpt1/2 double KO mice or Tie2 KO mice, induced during late gestation to overcome embryonic lethality, impaired vasa recta bundle formation was seen with a specific lack of ascending vasa recta [121]. Angpt2 showed, unlike VEGF and Angpt1, not to be vital for embryonic vascular development, yet necessary in postnatal vascular remodeling [122].…”