Glaucoma is a leading cause of preventable blindness in the world (30,46). Elevated intraocular pressure (IOP) is one of the strongest known risk factors (41) and can cause glaucoma in animal models (6). IOP elevation in human glaucoma results from increased resistance to aqueous-humor drainage (36). Although the etiology of glaucoma is complex, the result is death of retinal ganglion cells and loss of vision (31). Primary open-angle glaucoma (POAG) is the most common form of glaucoma in the United States and affects up to 1 to 2% of people over 40 years of age (47).Multiple genetic loci are reported to contribute to POAG (32,34,42,49,51,52). Disease-associated mutations have been identified in the myocilin gene, MYOC (14, 43). Studies from a broad range of ethnic backgrounds generally agree that MYOC mutations are responsible for approximately 3% of adult-onset POAG and a greater proportion of juvenile-onset open-angle glaucoma (2, 14). Despite this, neither the normal function(s) of MYOC nor how MYOC mutations result in IOP elevation and glaucoma has been defined.MYOC has also been implicated in steroid-induced ocular hypertension with glaucoma. Steroid-induced ocular hypertension in response to glucocorticoid treatment occurs in as many as 40% of people treated with glucocorticoids (37, 53). MYOC is up regulated in cultured trabecular meshwork (TM; an ocular drainage structure) cells treated with glucocorticoids.Thus, MYOC was identified as a candidate to mediate glucocorticoid-induced glaucoma (26,28). Supporting this, IOP elevation (assessed as an increase in drainage structure resistance) is glucocorticoid inducible in some but not all human anterior segment perfusion cultured eyes. In these cultures, IOP elevation correlates with MYOC induction (8) and ultrastructural changes (9) in the TM. Cultured anterior segments that developed elevated IOP had MYOC induction, while those that did not develop elevated IOP had no MYOC induction (8). Similarly, monkeys treated with glucocorticoids develop ocular hypertension (13), and in at least some eyes glucocorticoids induce MYOC and cause ultrastructural changes in the TM (8).Further studies, which do not involve steroid use, also can support a role for elevated MYOC levels in IOP elevation and glaucoma. In some glaucoma patients, the TM has elevated MYOC levels and broadened MYOC distribution (24). Cultured human anterior segments perfused with recombinant MYOC are reported to develop elevated IOP, whereas those perfused with an equal amount of other proteins or denatured MYOC do not (12). Finally, in the albino Wistar rat strain, experimental IOP elevation did not induce ocular MYOC, suggesting that MYOC induction does not occur secondary to IOP elevation (1).Despite these circumstantial data, there is no direct in vivo evidence that elevated MYOC levels cause IOP elevation and glaucoma. The rat study mentioned above (1) does not exclude MYOC elevation as a secondary response to increased IOP in different settings (either in different genetic contexts or in respo...
The phosphoinositide 3-kinase (PI3K) family has multiple vascular functions, but the specific regulatory isoform supporting lymphangiogenesis remains unidentified. Here, we report that deletion of the Pik3r1 gene, encoding the regulatory subunits p85␣, p55␣, and p50␣ impairs lymphatic sprouting and maturation, and causes abnormal lymphatic morphology, without major impact on blood vessels. Pik3r1 deletion had the most severe consequences among gut and diaphragm lymphatics, which share the retroperitoneal anlage, initially suggesting that the Pik3r1 role in this vasculature is anlage-dependent. However, whereas lymphatic sprouting toward the diaphragm was arrested, lymphatics invaded the gut, where remodeling and valve formation were impaired. Thus, cell-origin fails to explain the phenotype. Only the gut showed lymphangiectasia, lymphatic up-regulation of the transforming growth factor- co-receptor endoglin, and reduced levels of mature vascular endothelial growth factor-C protein. Our data suggest that Pik3r1 isoforms are required for distinct steps of embryonic lymphangiogenesis in different organ microenvironments, whereas they are largely dispensable for hemangiogenesis.
Abstract-Notch signaling is critical for the development and maintenance of the cardiovasculature, with loss-of-function studies defining roles of Notch1 in the endothelial/hematopoietic lineages. No in vivo studies have addressed complementary gain-of-function strategies within these tissues to define consequences of Notch activation. We developed a transgenic model of Cre recombinase-mediated activation of a constitutively active mouse Notch1 allele (N1ICD ϩ ) and studied transgene activation in Tie2-expressing lineages. The in vivo phenotype was compared to effects of Notch1 activation on endothelial tubulogenesis, paracrine regulation of smooth muscle cell proliferation, and hematopoiesis. N1ICDϩ embryos showed midgestation lethality with defects in angiogenic remodeling of embryonic and yolk sac vasculature, cardiac development, smooth muscle cell investment of vessels, and hematopoietic differentiation. Angiogenic defects corresponded with impaired endothelial tubulogenesis in vitro following Notch1 activation and paracrine inhibition of smooth muscle cells when grown with Notch1-activated endothelial cells. Key Words: angiogenesis Ⅲ endothelium Ⅲ blood vessels Ⅲ heart development F ormation of the vasculature begins with specification of angiogenic precursors and blood islands in the visceral yolk sac, where there is a close association between primitive hematopoietic cells and developing endothelium. 1 Blood vessels develop by aggregation of angioblasts into a primitive network. 2 At embryonic day (E)7.0 to E7.5, the yolk sac vasculature develops, starting as scattered blood islands that fuse to form a vascular network. At E8.5, this network fuses with the embryonic vasculature, allowing for the passage of primitive erythroblasts and hematopoietic stem cells into the circulation. Vessel maturation involves complex remodeling, with proliferation and sprouting of new vessels via angiogenesis. Heart development starts at E7.5 to E8.0, with midline endothelial tubes forming a heart tube, which undergoes folding to generate a primitive heart with endocardium, myocardium, and pericardium. At E9.5, the heart is starting the septation process from the common atrial chamber and the primitive ventricle.Notch signaling plays a critical role in cardiovascular development. Endothelial-specific deletion of Notch1 results in embryonic lethality with vascular defects, 3 and Notch1-null mice have defective vascular remodeling. A Notch ligand, Delta-like 4 (Dll4), is expressed in arterial endothelium, 4,5 and haploinsufficiency of Dll4 is associated with vascular defects and embryonic lethality. 6 Targeted mutations in Delta1 and Jagged1 cause hemorrhaging 5 and vascular remodeling defects, 7 respectively. The NOTCH3 gene is mutated 8 in the human disorder CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy), which is manifested by stroke, vascular dementia, and arteriopathy.Given the widespread defects associated with dysregulated Notch signaling, it is unclear whether Notc...
Background: Our study characterizes Delta-like 1 (Dll1) in the adult mouse, particularly in normal versus injured vasculature, with the aid of the transgenic Dll1LacZ line. Methods: Normal mouse adult tissues or those from the Dll1LacZ reporter line were analyzed for Dll1 expression and promoter activity. Vascular tissue was analyzed before and after carotid artery ligation. Results: In wild-type mice, Dll1 transcript expression was widespread. Similarly, the Dll1LacZ reporter had β-galactosidase activity detectable in the cerebellum, cerebrum, spinal cord, liver, lung and cornea, although the normal adult vasculature had no reporter expression. Following arterial ligation, there was acute induction of Dll1LacZ reporter expression, both in the ligated left carotid artery, and the uninjured right contralateral artery. Expression returned to low/undetectable levels 4–10 days after arterial ligation. Conclusion: The expression of Dll1 in the adult mouse is more widespread than previously realized, although not in resting large arteries in the adult mouse. Following arterial injury, Dll1 promoter activity is induced selectively in the endothelial cells of both the injured artery and the contralateral uninjured artery. Our results show that while overall expression in the adult mouse is widespread, Dll1 may be selectively expressed in the endothelium of injured vasculature, similar to the endothelial-restricted expression of Dll4.
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