Ts in Microvascular Endothelial Dysfunction

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Endothelial cell dysfunction is increasingly being realized as the unifying mechanism of development and progression of chronic diabetic complications. Endothelial cells are critical for a complex array of functions such as providing a barrier between blood and tissues, maintaining growth and phenotypic characteristics of smooth muscle cells, balancing pro- and anti-inflammatory changes, and fluidity of blood. Alteration of endothelial function, therefore, may affect one or more of these properties. In diabetic microan-giopathy, endothelial dysfunction is exhibited as increased permeation, vasoconstriction, and increased synthesis of ECM proteins. Hyalinosis of arterioles and capillaries in diabetes suggests accelerated loss of microvascular endothelial cells and increased ECM deposition. Endothelial degeneration, together with pericyte loss, may bring about a proliferative response and successive elaboration of BM proteins. ETs are implicated in several parameters of microvascular endothelial dysfunction. Administration of ET antagonists has been shown to prevent increased permeability, vasoconstriction, and BM protein expression.

Permeability

We have previously demonstrated that ETs regulate vascular endothelial permeability. Such increased permeability was normalized by treatment with ET receptor antagonist and PKC blocker [4]. The mechanisms by which ETs regulate endothelial permeability are not fully understood. Increased permeability may be arbitrated through endothe-lial cell contraction. Administration of calcium has been shown to cause phosphorylation of MLCK and cell contracture in endothelial cells [7]. Augmented ET expression by high glucose levels could increase endothelial permeability through interaction with ETB receptor that is G protein coupled and increases calcium via augmented IP3. In addition to cell contracture, ETs could also increase permeability via an MLCK-independent retraction mechanism. In such a process, ET-mediated PKC activation is of great significance. PKC has been shown to phosphorylate actin-linking proteins, talin and vanculin, producing intercellular gaps and increased permeability [8].

Mitogenic Responses

ETs are potent mitogens for vascular endothelial cells. The mitogenic property of ETs was first demonstrated in the early 1990s by DNA synthesis assays. Administration of ET-1 was shown to induce DNA synthesis in brain capillary endothelial cells. It has been demonstrated that selective ETB receptor antagonist can prevent endothelial cell proliferation and migration. In addition to endothelial cells, ETs exhibit mitogenic property toward smooth muscle cells. One interesting difference between the signaling pathways for endothelial and smooth muscle cell proliferation is the involvement of ET receptor type. It has been demonstrated that mitogenic signals are mediated through respective predominant receptor type, that is, for endothelial cells, ETB, and for smooth muscle cells, ETA.

In addition to several in vitro studies, ex vivo and in vivo studies also demonstrate mitogenic effects of ETs. Several biochemical pathways may mediate such proliferative signals. ET-induced tyrosine phosphorylation of proteins, such as Src, focal adhesion kinase, and janus kinase, may be involved in these mitogenic responses. In addition, PKC-dependent activation of mitogen activated protein kinase (MAPK) family members may be important in the transduction of mitogenic signals.

ECM Protein Upregulation

A structural hallmark of diabetic microangiopathy is increased capillary BM thickening. Increased expression and decreased degradation of ECM proteins is believed to be critical in BM thickening. The major fibrogenic proteins involved in upregulation of ECM proteins are ETs, TGF-ß, and angiotensin II. We have previously demonstrated that high glucose concentration in endothelial cells and hyper-glycemia in diabetes leads to upregulation of ECM proteins, fibronectin (FN) and collagen, via ET alteration. Further more, recent studies suggest that TGF-b and angiotensin II may also cause increased expression of ECM proteins through ETs. Studies from our laboratory demonstrate that ETs activate NF-kB and AP-1 in target organs and in cultured microvascular endothelial cells leading to FN upregulation [9]. It should be noted, however, that parallel activation of PKC and MAPK family by ETs may also be involved in increased FN expression.

In addition of direct upregulation of ECM proteins such as FN, ETs may also regulate composition of ECM. Recently, we have demonstrated that ETs regulate preferential expression of oncofetal FN, a splice variant of FN [10]. Oncofetal FN is exclusively expressed in proliferating tissues such as embryos and tumors and has recently been proposed to be a marker of tumoral angiogenesis. We have also shown that ET-mediated oncofetal FN is involved in microvascular endothelial cell proliferation. The mechanism by which ET-mediated oncofetal FN regulates cellular proliferation is still obscure. However, recent studies from our laboratory suggest a potential role of oncofetal FN in VEGF expression.

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