Mechanisms of Antiangiogenic-Induced Arterial Hypertension

Mourad, Jean‐Jacques; Lévy, Bernard

doi:10.1007/s11906-011-0206-y

Cited by 35 publications

(20 citation statements)

References 39 publications

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“…Hypertension is a common side effect of antiangiogenic therapy and can be attributed in part to diminution of the microvasculature (26,27). Although we did not observe any identifiable vascular density or structural abnormalities in several DCKO tissues examined ( Fig.…”

Section: Resultsmentioning

confidence: 65%

Endothelial cell FGF signaling is required for injury response but not for vascular homeostasis

Oladipupo

Smith

Santeford

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

119

107

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Endothelial cells (ECs) express fibroblast growth factor receptors (FGFRs) and are exquisitely sensitive to FGF signals. However, whether the EC or another vascular cell type requires FGF signaling during development, homeostasis, and response to injury is not known. Here, we show that Flk1-Cre or Tie2-Cre mediated deletion of FGFR1 and FGFR2 (Fgfr1/2Flk1-Cre or Fgfr1/ 2 Tie2-Cre mice), which results in deletion in endothelial and hematopoietic cells, is compatible with normal embryonic development. As adults, Fgfr1/2 Flk1-Cre mice maintain normal blood pressure and vascular reactivity and integrity under homeostatic conditions. However, neovascularization after skin or eye injury was significantly impaired in both Fgfr1/2Flk1-Cre and Fgfr1/2Tie2-Cre mice, independent of either hematopoietic cell loss of FGFR1/2 or vascular endothelial growth factor receptor 2 (Vegfr2) haploinsufficiency. Also, impaired neovascularization was associated with delayed cutaneous wound healing. These findings reveal a key requirement for cell-autonomous EC FGFR signaling in injuryinduced angiogenesis, but not for vascular homeostasis, identifying the EC FGFR signaling pathway as a target for diseases associated with aberrant vascular proliferation, such as age-related macular degeneration, and for modulating wound healing without the potential toxicity associated with direct manipulation of systemic FGF or VEGF activity.choroidal neovascularization | oxygen-induced retinopathy | retinopathy of prematurity | neoangiogenesis N eovascularization is critical for tissue repair and pathological conditions, including aberrant ocular angiogenesis and cancer (1-4). Although FGF signaling has been prominently implicated in these processes based on genetic inactivation experiments in mice and in vitro studies, the functional in vivo requirement of this pathway in the endothelial cell (EC) vs. other vascular cell types is not known (5-8).The FGF family is composed of 18 signaling ligands, which interact with four cell surface tyrosine kinase receptors. FGF receptor (FGFR) signaling regulates many biological processes, including survival, differentiation, proliferation, and angiogenesis through the activation of RAS-RAF-MAPK, PI3K, STAT, and PLC gamma pathways (6, 9). The EC response to FGF signals is well described in in vitro models of angiogenesis (10, 11). Moreover, previous gene expression analysis showed that Fgfr1 and Fgfr2 were the predominant Fgfrs in ECs (5), whereas Fgfr3 was sparsely detected (12, 13) and Fgfr4 expression was not reported (8). To this end, and given the critical role of FGFRs 1 and 2 during embryonic development, we tested the hypothesis that EC FGFR1/2 may play a key role during vascular development, homeostasis, and response to injury.Studies aimed at understanding the functional requirement of vascular FGF signaling have demonstrated a critical role in homeostasis and angiogenesis (14-16). In these studies, in vivo expression of an adenoviral-based soluble FGF trap (sFGFR) or a dominant inhibitor of all FGFRs (FGF...

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Section: Resultsmentioning

confidence: 65%

Endothelial cell FGF signaling is required for injury response but not for vascular homeostasis

Oladipupo

Smith

Santeford

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

119

107

View full text Add to dashboard Cite

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“…Hypertension has been commonly reported in all clinical trials testing inhibitors of angiogenesis with an incidence ranging from 11% to 43% in all studies. 26,27 The mechanism of elevated blood pressure in patients treated with antiangiogenic agents is not fully understood but probably involves endothelial dysfunction and capillary rarefaction. 26 Taken together, our findings have therapeutic implications for treatment strategies in hypertension and modulation of miRNA activity using antagomirs (miRNA inhibitor), or lipidbased nanoparticle delivery of miRNAs seems efficient.…”

Section: Discussionmentioning

confidence: 99%

miR-30a Regulates Endothelial Tip Cell Formation and Arteriolar Branching

et al. 2013

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Microvascular rarefaction increases vascular resistance and pressure in systemic arteries and is a hallmark of fixed essential hypertension. Preventing rarefaction by activation of angiogenic processes could lower blood pressure. Endothelial tip cells in angiogenic sprouts direct branching of microvascular networks; the process is regulated by microRNAs, particularly the miR-30 family. We investigated the contribution of miR-30 family members in arteriolar branching morphogenesis via delta-like 4 (Dll4)-Notch signaling in a zebrafish model. The miR-30 family consists of 5 members (miR-30a-e). Loss-of-function experiments showed that only miR-30a reduced growth of intersegmental arterioles involving impaired tip cell function. Overexpression of miR-30a stimulated tip cell behavior resulting in augmented branching of intersegmental arterioles. In vitro and in vivo reporter assays showed that miR-30a directly targets the Notch ligand Dll4, a key inhibitor of tip cell formation. Coadministration of a Dll4 targeting morpholino in miR-30a morphants rescued the branching defects. Conversely, conditional overexpression of Notch intracellular domain restored arteriolar branching in miR-30a gain-of-function embryos. In human endothelial cells, loss of miR-30a increased DLL4 protein levels, activated Notch signaling as indicated in Notch reporter assays, and augmented Notch downstream effector, HEY2 and EFNB2 (ephrin-B2), expression. In spheroid assays, miR-30a loss- and gain-of-function affected tip cell behavior, consistent with miR-30a targeting Dll4. Our data suggest that miR-30a stimulates arteriolar branching by downregulating endothelial Dll4 expression, thereby controlling endothelial tip cell behavior. These findings could have relevance to the rarefaction process and, therefore, to hypertension.

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“…Threshold values for AHT are lower with hBP (i.e. 135/85 mmHg) than the office BP (i.e 140/90 mmHg) [4]. Although the use of hBP is recommended to diagnose AHT, both the measurement protocol and thresholds values for AHT could greatly influence the detection and management of AHT during AAG therapy.…”

Section: Discussionmentioning

confidence: 99%

“…The mechanism of increased arterial blood pressure (BP) with treatment using AAG drugs is not fully understood, this mechanism is multifactorial, and includes endothelial dysfunction, capillary rarefaction and dysautonomia [4]. Vascular endothelial growth factor (VEGF) signaling represents a critical step in the process of angiogenesis [5], and agents targeting VEGF are being extensively investigated as anticancer therapy [6].…”

Section: Introductionmentioning

confidence: 99%

“…Mourad et al have shown that mean BP was increased after 6 months of AAG therapy compared with baseline, from 129 ± 13/75 ± 7 mmHg to 145 ± 17/82 ± 7 mmHg for systolic BP and diastolic BP respectively (p<0.0001) [10]. For patients treated with AAG, home blood pressure monitoring (HBPM) allows a better BP control, fewer complications and improved overall survival [4,11] and the role of hypertension in determining the risk of coronary artery disease is well known [12]. Several studies have suggested that early blood pressure rise was associated with better antitumoral efficacy and improved prognosis, making this commonly observed effect a promising marker of efficacy [13].…”

Section: Introductionmentioning

confidence: 99%

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