Platelet-derived growth factor receptors on macrovascular endothelial cells mediate relaxation via nitric oxide in rat aorta.

Cunningham, Leslie; Brecher, Peter; Cohen, Ran

doi:10.1172/jci115667

Cited by 46 publications

(19 citation statements)

References 32 publications

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“…Most importantly, different PDGF ligands produce different cellular responses even when acting on a common receptor [140]. PDGF can stimulate mitogenesis in smooth muscle, NO-dependent vasorelaxation in endothelium-intact aortic rings [141], and microvascular angiogenesis in invasive breast cancer [142]. PDGF-BB can transform smooth muscle to a less contractile phenotype, and is crucial for proper lung development of neonatal rats [28, 143].…”

Section: Receptor Tyrosine Kinase-dependent Vasotrophic Factorsmentioning

confidence: 99%

Vasotrophic Regulation of Age-Dependent Hypoxic Cerebrovascular Remodeling

Silpanisong¹,

Pearce²

2013

CVP

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Hypoxia can induce functional and structural vascular remodeling by changing the expression of trophic factors to promote homeostasis. While most experimental approaches have been focused on functional remodeling, structural remodeling can reflect changes in the abundance and organization of vascular proteins that determine functional remodeling. Better understanding of age-dependent hypoxic macrovascular remodeling processes of the cerebral vasculature and its clinical implications require knowledge of the vasotrophic factors that influence arterial structure and function. Hypoxia can affect the expression of transcription factors, classical receptor tyrosine kinase factors, non-classical G-protein coupled factors, catecholamines, and purines. Hypoxia’s remodeling effects can be mediated by Hypoxia Inducible Factor (HIF) upregulation in most vascular beds, but alterations in the expression of growth factors can also be independent of HIF. PPARγ is another transcription factor involved in hypoxic remodeling. Expression of classical receptor tyrosine kinase ligands, including vascular endothelial growth factor, platelet derived growth factor, fibroblast growth factor and angiopoietins, can be altered by hypoxia which can act simultaneously to affect remodeling. Tyrosine kinase-independent factors, such as transforming growth factor, nitric oxide, endothelin, angiotensin II, catecholamines, and purines also participate in the remodeling process. This adaptation to hypoxic stress can fundamentally change with age, resulting in different responses between fetuses and adults. Overall, these mechanisms integrate to assure that blood flow and metabolic demand are closely matched in all vascular beds and emphasize the view that the vascular wall is a highly dynamic and heterogeneous tissue with multiple cell types undergoing regular phenotypic transformation.

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Section: Receptor Tyrosine Kinase-dependent Vasotrophic Factorsmentioning

confidence: 99%

Vasotrophic Regulation of Age-Dependent Hypoxic Cerebrovascular Remodeling

Silpanisong¹,

Pearce²

2013

CVP

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“…sphingosine-1-phosphate/EDG-1, and angiopoietin/Tie-2, have been shown to induce NO production. NO also has been shown to mediate downstream signaling, angiogenesis, and vascular SMC relaxation induced by these pathways (7,8,53). TGF-β1, which has been shown to mediate mural cell differentiation, also stimulates NO production through upregulation of eNOS transcription and stabilization of eNOS mRNA (54).…”

Section: Figurementioning

confidence: 99%

NO mediates mural cell recruitment and vessel morphogenesis in murine melanomas and tissue-engineered blood vessels

Kashiwagi¹,

Izumi²,

Gohongi³

et al. 2005

J. Clin. Invest.

174

131

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NO has been shown to mediate angiogenesis; however, its role in vessel morphogenesis and maturation is not known. Using intravital microscopy, histological analysis, α-smooth muscle actin and chondroitin sulfate proteoglycan 4 staining, microsensor NO measurements, and an NO synthase (NOS) inhibitor, we found that NO mediates mural cell coverage as well as vessel branching and longitudinal extension but not the circumferential growth of blood vessels in B16 murine melanomas. NO-sensitive fluorescent probe 4,5-diaminofluorescein imaging, NOS immunostaining, and the use of NOS-deficient mice revealed that eNOS in vascular endothelial cells is the predominant source of NO and induces these effects. To further dissect the role of NO in mural cell recruitment and vascular morphogenesis, we performed a series of independent analyses. Transwell and under-agarose migration assays demonstrated that endothelial cell-derived NO induces directional migration of mural cell precursors toward endothelial cells. An in vivo tissue-engineered blood vessel model revealed that NO mediates endothelial-mural cell interaction prior to vessel perfusion and also induces recruitment of mural cells to angiogenic vessels, vessel branching, and longitudinal extension and subsequent stabilization of the vessels. These data indicate that endothelial cell-derived NO induces mural cell recruitment as well as subsequent morphogenesis and stabilization of angiogenic vessels.

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“…Early study showed that PDGF-BB can dilate rat aorta and mesenteric arteries. 26 However, we found that PDGF-AA impairs endothelium-dependent vasodilation. The difference may be caused by the differential expressions of PDGFRα and PDGFRβ in different vascular bed and different downstream signaling pathways.…”

Section: Discussionmentioning

confidence: 61%

Bone Morphogenic Protein 4-Smad–Induced Upregulation of Platelet-Derived Growth Factor AA Impairs Endothelial Function

Zhang

Wang

et al. 2016

ATVB

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Bone morphogenic protein 4 (BMP4), which falls into the transforming growth factors-β (TGF-β) superfamily, plays an essential role in cartilage formation, bone mineralization, and early embryonic development.1 BMP4 and BMP2 both bind to the BMPRII, which then dimerize with BMPRI. The dimerization and phosphorylation of BMPRI leads to the activation of canonical Smad1/5/8 in the cytoplasm. Smad1/5/8 associates with co-Smad, Smad4, and translocate to the nucleus. This Smad complex will bind to the Smadresponsive element and induce the transcription of Smad-target genes.3 In addition to the canonical Smad signaling, BMP4 also activates ERK (extracellular signal-regulated kinases) and p38/JNK non-Smad pathway in certain cell types for finetuning of its action. 3,4 In the cardiovascular system, mutations or anomalies of BMP are associated with the development of pulmonary hypertension, cardiovascular calcification, stroke, and type 2 diabetes mellitus. 5 In the vasculature, BMP4 acts as a proinflammatory cytokine to stimulate superoxide anion production and exerts inflammatory effects through NADPH oxidases. BMP4 expression is upregulated in human calcified atherosclerotic plaques, 6 and oscillatory sheer stress induces endothelial expression of BMP4.7 BMP4 increases the expression and activity of cyclooxygenase-2 and, in turn, the production of vasoconstrictive prostanoids to impair endothelial function in arteries from rats, mice, and human.8 BMP4 also induces endothelial cell apoptosis through oxidative stress, 9 and it stimulates protein carbonylation involved in endothelial dysfunction.10 BMP4 enhances foam cell formation by © 2016 American Heart Association, Inc. Objective-Bone morphogenic protein 4 (BMP4) is an important mediator of endothelial dysfunction in cardio-metabolic diseases, whereas platelet-derived growth factors (PDGFs) are major angiogenic and proinflammatory mediator, although the functional link between these 2 factors is unknown. The present study investigated whether PDGF mediates BMP4-induced endothelial dysfunction in diabetes mellitus. Approach and Results-We generated Ad-Bmp4 to overexpress Bmp4 and Ad-Pdgfa-shRNA to knockdown Pdgfa in mice through tail intravenous injection. SMAD4-shRNA lentivirus, SMAD1-shRNA, and SMAD5 shRNA adenovirus were used for knockdown in human and mouse endothelial cells. We found that PDGF-AA impaired endothelium-dependent vasodilation in aortas and mesenteric resistance arteries. BMP4 upregulated PDGF-AA in human and mouse endothelial cells, which was abolished by BMP4 antagonist noggin or knockdown of SMAD1/5 or SMAD4. BMP4-impared relaxation in mouse aorta was also ameliorated by PDGF-AA neutralizing antibody. Tail injection of Ad-Pdgfa-shRNA ameliorates endothelial dysfunction induced by Bmp4 overexpression (Ad-Bmp4) in vivo. Serum PDGF-AA was elevated in both diabetic patients and diabetic db/db mice compared with nondiabetic controls. Pdgfa-shRNA or Bmp4-shRNA adenovirus reduced serum PDGF-AA concentration in db/db mice. PDGF-AA neutralizing antibody or ...

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Platelet-derived growth factor receptors on macrovascular endothelial cells mediate relaxation via nitric oxide in rat aorta.

Cited by 46 publications

References 32 publications

Vasotrophic Regulation of Age-Dependent Hypoxic Cerebrovascular Remodeling

Vasotrophic Regulation of Age-Dependent Hypoxic Cerebrovascular Remodeling

NO mediates mural cell recruitment and vessel morphogenesis in murine melanomas and tissue-engineered blood vessels

Bone Morphogenic Protein 4-Smad–Induced Upregulation of Platelet-Derived Growth Factor AA Impairs Endothelial Function

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