Eye lymphatic defects induced by bone morphogenetic protein 9 deficiency have no functional consequences on intraocular pressure

Abstract

Aqueous humor drainage is essential for the regulation of intraocular pressure (IOP), a major risk factor for glaucoma. The Schlemm’s canal and the non-conventional uveoscleral pathway are known to drain aqueous humor from the eye anterior chamber. It has recently been reported that lymphatic vessels are involved in this process, and that the Schlemm’s canal responds to some lymphatic regulators. We have previously shown a critical role for bone morphogenetic protein 9 (BMP9) in lymphatic vessel maturation and valve formation, with repercussions in drainage efficiency. Here, we imaged eye lymphatic vessels and analyzed the consequences of Bmp9 (Gdf2) gene invalidation. A network of lymphatic vessel hyaluronan receptor 1 (LYVE-1)-positive lymphatic vessels was observed in the corneolimbus and the conjunctiva. In contrast, LYVE-1-positive cells present in the ciliary bodies were belonging to the macrophage lineage. Although enlarged conjunctival lymphatic trunks and a reduced valve number were observed in Bmp9-KO mice, there were no morphological differences in the Schlemm’s canal compared to wild type animals. Moreover, there were no functional consequences on IOP in both basal control conditions and after laser-induced ocular hypertonia. Thus, the BMP9-activated signaling pathway does not constitute a wise target for new glaucoma therapeutic strategies.

Lymphatics in Eye Fluid Homeostasis: Minor Contributors or Significant Actors?

“…A denser distribution of conjunctival lymphatic vessels at the nasal side of the eyeball was previously reported in a model of induced corneal lymphangiogenesis [28]. The observation of a temporal-nasal polarized distribution has recently been confirmed by innovative techniques, such as LSFM, combined or not with optical clearing of the intact pigmented mouse eyeball, that have allowed the 3D visualization of the lymphatic topography of the whole mouse ocular surface lymphatic network [27,29] (Figure 2).…”

“…In these studies, the bulbar conjunctiva covering the bulbar sclera, was observed to display a rich network of lymphatic vessels composed of initial lymphatics that drains into LYVE-1-positive precollectors containing valves [27]. As illustrated on the scheme in Figure 3, the ocular surface lymphatics were observed to converge at the nasal canthus by large lymphatic trunks displaying lower LYVE-1 expression and draining either the dorsal or the ventral side of the eyeball [27].…”

“…Moreover, these draining lymphatic networks exhibit a different spatial organization on each side of the nictitating membrane depending on the drained ventral or dorsal region of the eyeball, reflecting in addition, a dorsal-ventral polarization (Figure 3). A dense and ramified conjunctival network presenting many circular loops drains the ventral part of the eyeball whereas a less developed vessel network converging in a large individual lymphatic trunk drains the dorsal part of the eyeball [27]. These two different bulbar conjunctival lymphatic networks were symmetrically opposite when comparing the right and the left eyes [27].…”

“…Corneolimbal lymphatics are LYVE-1-positive and display the conventional oak leaf-like cells with button-like interendothelial junctions. They can develop valves indicating that some of these vessels are likely precollectors [26,27]. Limbal lymphatics have connections with the conjunctival network covering the bulbar conjunctiva.…”

“…In these studies, the bulbar conjunctiva covering the bulbar sclera, was observed to display a rich network of lymphatic vessels composed of initial lymphatics that drains into LYVE-1-positive precollectors containing valves [27]. As illustrated on the scheme in Figure 3, the ocular surface lymphatics were observed to converge at the nasal canthus by large lymphatic trunks displaying lower LYVE-1 expression and draining either the dorsal or the ventral side of the eyeball [27]. Moreover, these draining lymphatic networks exhibit a different spatial organization on each side of the nictitating membrane depending on the drained ventral or dorsal region of the eyeball, reflecting in addition, a dorsal-ventral polarization (Figure 3).…”