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Vitamin D and Regulation of Pericyte Function
Başlık:
Vitamin D and Regulation of Pericyte Function
Yazar:
Jamali, Nasim, author.
ISBN:
9780438029828
Yazar Ek Girişi:
Fiziksel Tanımlama:
1 electronic resource (372 pages)
Genel Not:
Source: Dissertation Abstracts International, Volume: 79-10(E), Section: B.
Advisors: Nader Sheibani Committee members: Peiman Hematti; Bo Liu; Ronald R. Magness; Donna M. Peters.
Özet:
Vitamin D deficiency has been linked to pathogenesis of many diseases including cardiovascular, cancer, and various eye diseases. In recent years, important roles for vitamin D in regulation of immune function, inflammation, angiogenesis, and aging have been demonstrated. Vitamin D and its analogs have also been used for treatment of various cancers and chronic diseases. However, the underlying mechanisms involved remain poorly understood. We previously showed vitamin D is a potent inhibitor of angiogenesis. This is consistent with the important roles proposed for vitamin D in regulation of vascular function and attenuation of tumor growth. The important nutritional value of vitamin D, various abnormalities linked to its deficiency, and its various therapeutic benefits are addressed in chapter one. I have explored the potential role of vitamin D as a regulator of angiogenesis and vascular cell function, and the role vitamin D receptor plays in these activities in subsequent chapters.
The majority of vitamin D action is mediated through vitamin D receptor (Vdr). However, the role Vdr expression plays in vascular development and inhibition of neovascularization by vitamin D remained unknown. In chapter two, I determined the impact of Vdr expression on postnatal retinal vasculature development and retinal neovascularization using wild type (Vdr +/+) and Vdr-deficient (Vdr -/-) mice. These results indicated no significant effect on postnatal retinal vascular development in Vdr -/- mice up to postnatal day 21 (P21) compared with Vdr +/+ mice. However, a significant decrease was observed in the ratio of endothelial cells to pericyte (EC/PC) at P42, when the remodeling and pruning of the retinal vasculature is complete, in Vdr -/- mice compared with Vdr +/+ mice. This was attributed to an increase in density of PC and a decrease in density of EC. Although Vdr deficiency did not show a significant impact on vessel obliteration and retinal neovascularization, the Vdr expression was essential for inhibition of retinal neovascularization by vitamin D. In addition, the adverse impact of vitamin D treatment on bodyweight was also dependent on Vdr expression. Thus, Vdr expression plays a significant role during retinal vascular development and inhibition of neovascularization and adverse systemic effects of vitamin D.
Our previous studies indicated that calcitriol has no significant effect on retinal EC function in culture. However, calcitriol inhibited capillary morphogenesis of EC in Matrigel. As PC, play essential roles during angiogenesis, including vascular maturation and stabilization of newly forming blood vessels, in chapter three, I investigated the impact of calcitriol on retinal PC function. These results demonstrated that calcitriol decreased proliferation and migration of retinal PC in culture. Although apoptosis of retinal PC were not affected by calcitriol, an increase in G0/G1cell cycle arrest was observed. Adhesion of PC to various extracellular matrix proteins (ECM) was also increased by calcitriol. Retinal PC expressed significantly higher level of Vdr compared with EC. Vdr -/- PC showed increased adhesion to the ECM proteins. Although, calcitriol failed to inhibit the proliferation of Vdr -/- retinal PC, it did inhibit their migration. Furthermore, incubation of retinal PC with calcitriol resulted in increased levels of vascular endothelial growth factor (VEGF). The antagonism of VEGF signaling partially restored the phenotype of PC incubated with calcitriol. Interestingly, incubation of PC with VEGF increased Vdr expression. Together, these results suggest an important role for PC as target of vitamin D action and attenuation of angiogenesis.
To further investigate whether the observed effects of calcitriol on PC is organ specific, I also evaluated the response of lung PC to calcitriol. Similar to retinal PC, calcitriol reduced proliferation and migration of lung PC as well as increased G1 arrest. However, adhesion to ECM proteins remained unchanged in lung PC incubated with calcitriol. Vdr -/- lung PC, similar to Vdr-/- retinal PC, were more adherent but less responsive to the calcitriol effects, compare to Vdr+/+ lung PC.
Taken together, these studies established an important role for vitamin D and its receptor in regulation of perivascular supporting cell function. I propose Vdr expression is important during maturation of developing vasculature by promoting the quiescence of pericytes that cover the newly formed blood vessels. I propose increased production of VEGF by PC in response to vitamin D promotes the heterodiamerization of VEGF and PDGF receptors on PC attenuating their proangiogenic signaling in PC. Delineating the signaling pathways, involved molecular mechanisms, and identification of genes that are target of vitamin D regulation in vascular cells, will identify novel pathways as target for regulation of vascular function and angiogenesis.
Notlar:
School code: 0262
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Yer Numarası | Demirbaş Numarası | Shelf Location | Lokasyon / Statüsü / İade Tarihi |
---|---|---|---|
XX(678005.1) | 678005-1001 | Proquest E-Tez Koleksiyonu | Arıyor... |
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