SRF selectively controls tip cell invasive behavior in angiogenesis

Franco, Cláudio A.; Blanc, Jocelyne; Parlakian, Ara; Blanco, Raquel; Aspalter, Irene M.; Kazakova, Natalia; Diguet, Nicolas; Mylonás, Elena; Gao-Li, Jacqueline; Vaahtokari, Anne; Penard-Lacronique, Virginie; Fruttiger, Marcus; Rosewell, Ian; Mericskay, Mathias; Gerhardt, Holger; Li, Zhenlin

doi:10.1242/dev.091074

Cited by 59 publications

(55 citation statements)

References 54 publications

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“…Accordingly, endothelial-specific deficiency of MRTFs caused incomplete formation of the primary vascular plexus of the developing retina 26 . Moreover, SRF, the main target of MRTF-A, has recently been identified as crucial for tip cell behaviour in sprouting angiogenesis upon VEGF-A stimulation 25 . Nevertheless, VEGF-A results in growth of immature and unstable capillaries 37 , as opposed to T 4-MRTF-A, pointing to a difference in signalling of both vessel growth factors.…”

Section: Discussionmentioning

confidence: 99%

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MRTF-A controls vessel growth and maturation by increasing the expression of CCN1 and CCN2

et al. 2014

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Gradual occlusion of coronary arteries may result in reversible loss of cardiomyocyte function (hibernating myocardium), which is amenable to therapeutic neovascularization. The role of myocardin-related transcription factors (MRTFs) co-activating serum response factor (SRF) in this process is largely unknown. Here we show that forced MRTF-A expression induces CCN1 and CCN2 to promote capillary proliferation and pericyte recruitment, respectively. We demonstrate that, upon G-actin binding, thymosin 4 (T 4), induces MRTF translocation to the nucleus, SRF-activation and CCN1/2 transcription. In a murine ischaemic hindlimb model, MRTF-A or T 4 promotes neovascularization, whereas loss of MRTF-A/B or CCN1-function abrogates the T 4 effect. We further show that, in ischaemic rabbit hindlimbs, MRTF-A as well as T 4 induce functional neovascularization, and that this process is inhibited by angiopoietin-2, which antagonizes pericyte recruitment. Moreover, MRTF-A improves contractile function of chronic hibernating myocardium of pigs to a level comparable to that of transgenic pigs overexpressing T 4 (T 4tg). We conclude that MRTF-A promotes microvessel growth (via CCN1) and maturation (via CCN2), thereby enabling functional improvement of ischaemic muscle tissue.

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Section: Discussionmentioning

confidence: 99%

“…However, MRTF coactivaton of SRF induces pro-angiogenic factors such as CCN1 (Cyr61) 22 and maturation factors such as connective tissue growth factor (CTGF) 23,24 . Moreover, SRF controls tip cell behaviour in angiogenesis 25,26 , indicating a role of MRTF-SRF in vascular growth and maintenance.…”

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confidence: 99%

MRTF-A controls vessel growth and maturation by increasing the expression of CCN1 and CCN2

et al. 2014

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“…Murine retinal angiogenesis requires the SRF transcription factor [6], [7], [8]. SRF is ubiquitously expressed and fulfills many essential functions [9].…”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, these SRF cofactors have different effects on angiogenesis. Murine endothelial Srf depletion results in characteristic phenotypes in early post-natal and adult retinae [7], [8], which are mimicked by deletion of Mrtf-a and Mrtf-b , but not by single or double deletion of the Elk1 and Elk4 genes [8]. The murine phenotypes upon post-natal endothelial depletion of SRF or MRTF-A/-B reflect some pathological features exhibited by human patients suffering from FEVR (familial exudative vitreoretinopathies) and AMD (adult macular degeneration) [8].…”

Section: Introductionmentioning

confidence: 99%

Elk3 Deficiency Causes Transient Impairment in Post-Natal Retinal Vascular Development and Formation of Tortuous Arteries in Adult Murine Retinae

et al. 2014

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Serum Response Factor (SRF) fulfills essential roles in post-natal retinal angiogenesis and adult neovascularization. These functions have been attributed to the recruitment by SRF of the cofactors Myocardin-Related Transcription Factors MRTF-A and -B, but not the Ternary Complex Factors (TCFs) Elk1 and Elk4. The role of the third TCF, Elk3, remained unknown. We generated a new Elk3 knockout mouse line and showed that Elk3 had specific, non-redundant functions in the retinal vasculature. In Elk3(−/−) mice, post-natal retinal angiogenesis was transiently delayed until P8, after which it proceeded normally. Interestingly, tortuous arteries developed in Elk3(−/−) mice from the age of four weeks, and persisted into late adulthood. Tortuous vessels have been observed in human pathologies, e.g. in ROP and FEVR. These human disorders were linked to altered activities of vascular endothelial growth factor (VEGF) in the affected eyes. However, in Elk3(−/−) mice, we did not observe any changes in VEGF or several other potential confounding factors, including mural cell coverage and blood pressure. Instead, concurrent with the post-natal transient delay of radial outgrowth and the formation of adult tortuous arteries, Elk3-dependent effects on the expression of Angiopoietin/Tie-signalling components were observed. Moreover, in vitro microvessel sprouting and microtube formation from P10 and adult aortic ring explants were reduced. Collectively, these results indicate that Elk3 has distinct roles in maintaining retinal artery integrity. The Elk3 knockout mouse is presented as a new animal model to study retinal artery tortuousity in mice and human patients.

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“…Previously, by using Srf iECKO and Mrtf-a (−/−) Mrtf-b iECKO mice, an endothelial role of murine SRF and its MRTF cofactors was shown for retinal angiogenesis (10,11).…”

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confidence: 99%

Endothelial depletion of murine SRF/MRTF provokes intracerebral hemorrhagic stroke

Weinl

Vega

Riehle

et al. 2015

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

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Intracerebral hemorrhagic stroke and vascular dementia are age- and hypertension-associated manifestations of human cerebral small vessel disease (SVD). Cerebral microvessels are formed by endothelial cells (ECs), which are connected through tight junctions, adherens junctions, and stabilizing basement membrane structures. These endothelial connections ensure both vessel stability and blood–brain barrier (BBB) functions, the latter enabling selective exchange of ions, bioactive molecules, and cells between the bloodstream and brain tissue. SrfiECKO mice, permitting conditional EC-specific depletion of the transcription factor Serum Response Factor (SRF), suffer from loss of BBB integrity and intracerebral hemorrhaging. Cerebral microbleeds and larger hemorrhages developed upon postnatal and adult depletion of either SRF or its cofactors Myocardin Related Transcription Factor (MRTF-A/-B), revealing essential requirements of ongoing SRF/MRTF activity for maintenance of cerebral small vessel integrity. In vivo magnetic resonance imaging allowed detection, localization, and time-resolved quantification of BBB permeability and hemorrhage formation in SrfiECKO brains. At the molecular level, direct and indirect SRF/MRTF target genes, encoding structural components of tight junctions (Claudins and ZO proteins), adherens junctions (VE-cadherin, α-Actinin), and the basement membrane (Collagen IV), were down-regulated upon SRF depletion. These results identify SRF and its MRTF cofactors as major transcriptional regulators of EC junctional stability, guaranteeing physiological functions of the cerebral microvasculature. We hypothesize that impairments in SRF/MRTF activity contribute to human SVD pathology.

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SRF selectively controls tip cell invasive behavior in angiogenesis

Cited by 59 publications

References 54 publications

MRTF-A controls vessel growth and maturation by increasing the expression of CCN1 and CCN2

MRTF-A controls vessel growth and maturation by increasing the expression of CCN1 and CCN2

Elk3 Deficiency Causes Transient Impairment in Post-Natal Retinal Vascular Development and Formation of Tortuous Arteries in Adult Murine Retinae

Endothelial depletion of murine SRF/MRTF provokes intracerebral hemorrhagic stroke

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