D-glucose stimulation of L-arginine transport and nitric oxide synthesis results from activation of mitogen-activated protein kinases p42/44 and Smad2 requiring functional type II TGF-β receptors in human umbilical vein endothelium
✍ Scribed by Rodrigo Vásquez; Marcelo Farías; José Luis Vega; Rody San Martin; Andrea Vecchiola; Paola Casanello; Luis Sobrevia
- Publisher
- John Wiley and Sons
- Year
- 2007
- Tongue
- English
- Weight
- 273 KB
- Volume
- 212
- Category
- Article
- ISSN
- 0021-9541
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✦ Synopsis
Abstract
Elevated extracellular D‐glucose increases transforming growth factor β1 (TGF‐β1) release from human umbilical vein endothelium (HUVEC). TGF‐β1, via TGF‐β receptors I (TβRI) and TβRII, activates Smad2 and mitogen‐activated protein kinases p44 and p42 (p42/44^mapk^). We studied whether D‐glucose‐stimulation of L‐arginine transport and nitric oxide synthesis involves TGF‐β1 in primary cultures of HUVEC. TGF‐β1 release was higher (∼1.6‐fold) in 25 mM (high) compared with 5 mM (normal) D‐glucose. TGF‐β1 increases L‐arginine transport (half maximal effect ∼1.6 ng/ml) in normal D‐glucose, but did not alter high D‐glucose‐increased L‐arginine transport. TGF‐β1 and high D‐glucose increased hCAT‐1 mRNA expression (∼8‐fold) and maximal transport velocity (V~max~), L‐[^3^H]citrulline formation from L‐[^3^H]arginine (index of NO synthesis) and endothelial NO synthase (eNOS) protein abundance, but did not alter eNOS phosphorylation. TGF‐β1 and high D‐glucose increased p42/44^mapk^ and Smad2 phosphorylation, an effect blocked by PD‐98059 (MEK1/2 inhibitor). However, TGF‐β1 and high D‐glucose were ineffective in cells expressing a truncated, negative dominant TβRII. High D‐glucose increases L‐arginine transport and eNOS expression following TβRII activation by TGF‐β1 involving p42/44^mapk^ and Smad2 in HUVEC. Thus, TGF‐β1 could play a crucial role under conditions of hyperglycemia, such as gestational diabetes mellitus, which is associated with fetal endothelial dysfunction. J. Cell. Physiol. 212:626–632, 2007. © 2007 Wiley‐Liss, Inc.