Physical Forces and their Translation into Molecular Mechanisms

Schäper, Wolfgang; Pipp, Frederic; Scholz, Dimitri; Boehm, Stefanie; Deindl, Elisabeth; Barancik, Miroslaw; Eitenmueller, Inka; Ziegelhoeffer, Tibor; Schmitz‐Rixen, Thomas

doi:10.1007/1-4020-8126-x_5

Cited by 8 publications

(5 citation statements)

References 106 publications

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“…14 The markedly negative effect on blood flow recovery after FAL in eNOS-targeted mice 15 has led authors to conclude that eNOS plays a significant role in arteriogenesis. However, morphometric studies of collateral arteries proper of eNOS-targeted mice did not find inhibition of arteriogenesis (collateral vessels had enlarged to the same extent as in WT mice 4,16 ). Furthermore, the very slow recovery of blood flow after femoral occlusion was instantly normalized by acute injections of the vasodilator SNAP as we demonstrate in this study (Day 14 and Day 21).…”

Section: Discussioncontrasting

confidence: 46%

Effects of Endogenous Nitric Oxide and of DETA NONOate in Arteriogenesis

Troidl¹,

Tribulova²,

Cai³

et al. 2010

Journal of Cardiovascular Pharmacology

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Previous studies showed that targeted endothelial nitric oxide synthase (eNOS) disruption in mice with femoral artery occlusion does not impede and transgenic eNOS overexpression does not stimulate collateral artery growth after femoral artery occlusion, suggesting that nitric oxide from eNOS does not play a role in arteriogenesis. However, pharmacologic nitric oxide synthase inhibition with L-NAME markedly blocks arteriogenesis, suggestive of an important role of nitric oxide. To solve the paradox, we studied targeted deletion of eNOS and of inducible nitric oxide synthase (iNOS) in mice and found that only iNOS knockout could partially inhibit arteriogenesis. However, the combination of eNOS knockout and treatment with the iNOS inhibitor L-NIL completely abolished arteriogenesis. mRNA transcription studies (reverse transcriptase-polymerase chain reaction) performed on collateral arteries of rats showed that eNOS and especially iNOS (but not neural nitric oxide synthase) become upregulated in shear stress-stimulated collateral vessels, which supports the hypothesis that nitric oxide is necessary for arteriogenesis but that iNOS plays an important part. This was strengthened by the observation that the nitric oxide donor DETA NONOate strongly stimulated collateral artery growth, activated perivascular monocytes, and increased proliferation markers. Shear stress-induced nitric oxide may activate the innate immune system and activate iNOS. In conclusion, arteriogenesis is completely dependent on the presence of nitric oxide, a large part of it coming from mononuclear cells.

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Section: Discussioncontrasting

confidence: 46%

Effects of Endogenous Nitric Oxide and of DETA NONOate in Arteriogenesis

Troidl¹,

Tribulova²,

Cai³

et al. 2010

Journal of Cardiovascular Pharmacology

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“…Furthermore, Eitermueller et al found that collateralg rowthw as associatedw ith an upregulation of members of the Rho-kinase pathway confirming previous results (19,20). Since shearstresshas been shown to causeareorganisation of the endothelial cytoskeleton (21),itisofspecial interesttoknowthat the Rho-kinase pathway is involved in regulating actin dynamicsb ycontrolling the activity of cofilin (22,23), a protein whichhas been shown to be differentiallye xpressed in ECs and SMCs of growing collaterals (17,20). Actin dynamics playa ni mportant rolei nc ontrolling serum response factor (SRF) activity.STARS, amuscle-specific actin binding protein and activator of RhoA and SRF (24), has recently beenidentified by the group around Schaperingrowing collateral arteries (25).…”

Section: Mechanicalforcessignal Transductionpathways Andtranscriptiomentioning

confidence: 56%

“…These dataaltogetherindicate that neither hypoxia or ischemia nor hypoxia-associated processesl ikea ngiogenesis are necessary or aprerequisite for proper arteriogenesis. Therefore, it wasl ikelyt hat physicalf orces likep ressure-related stresses (circumferential, radial and longitudinal)a nd/or fluid shear stress experienced by collateral arteries duetoincreased blood floware triggering arterial growth (16)(17)(18).…”

Section: Hypoxia Andh Ypoxia-relatedprocessesmentioning

confidence: 99%

Arteriogenesis: A focus on signal transduction cascades and transcription factors

Deindl

2007

Thromb Haemost

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SummaryIn recent years intensive investigations have been performed to unravel the molecular mechanisms of collateral artery growth (arteriogenesis), a process designed by nature to compensate the devastating consequences of major arterial occlusions. Currently, a variety of gene products as well as signal transduction pathways involved in arteriogenesis have been identified. However, it is still not clear how the progression of cellular signals evoked by an increased blood flow and therefore mechanical stress proceeds. Literature research identified the transcription factors early growth response-1 (Egr-1) as well as serum response factor (SRF) and myocardin-related transcription factors (MRTFs) as liaisons connecting the key pathways of arteriogenesis, i.e.the Rho-kinase pathway and the MEK/ERK pathway, with each other as well as with downstream genes.

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“…2 This increased mechanical load is exerted on ECs (endothelial cells) of pre-existing arteriolar connections by the redirected blood flow caused by occlusion of a conductance artery. 3 Animal models, mainly for peripheral arteriogenesis, evidenced that increased shear stress results in activation of the arteriolar endothelium with subsequent upregulation of monocyte chemoattractant protein-1 (MCP-1) as well as ICAM1 presenting the prerequisite for monocyte recruitment, adhesion, and extravasation. [4][5][6] After extravasation, monocytes mature to macrophages, whereby M1 as well as M2 macrophages have been described to contribute to vascular remodeling.…”

mentioning

confidence: 99%

Arginase inhibition attenuates arteriogenesis and interferes with M2 macrophage accumulation

Lasch¹,

Caballero-Martinez²,

Troidl

et al. 2016

Laboratory Investigation

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L-Arginine is the common substrate for nitric oxide synthases (NOS) and arginase. Whereas the contribution of NOS to collateral artery growth (arteriogenesis) has been demonstrated, the functional role of arginase remains to be elucidated and was topic of the present study. Arteriogenesis was induced in mice by ligation of the femoral artery. Laser Doppler perfusion measurements demonstrated a significant reduction in arteriogenesis in mice treated with the arginase inhibitor nor-NOHA (N ω -hydroxy-nor-arginine). Accompanying in vitro results on murine primary arterial endothelial cells and smooth muscle cells revealed that nor-NOHA treatment interfered with cell proliferation and resulted in increased nitrate/ nitrite levels, indicative for increased NO production. Immuno-histological analyses on tissue samples demonstrated that nor-NOHA administration caused a significant reduction in M2 macrophage accumulation around growing collateral arteries. Gene expression studies on isolated growing collaterals evidenced that nor-NOHA treatment abolished the differential expression of Icam1 (intercellular adhesion molecule 1). From our data we conclude that arginase activity is essential for arteriogenesis by promoting perivascular M2 macrophage accumulation as well as arterial cell proliferation.

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Physical Forces and their Translation into Molecular Mechanisms

Cited by 8 publications

References 106 publications

Effects of Endogenous Nitric Oxide and of DETA NONOate in Arteriogenesis

Effects of Endogenous Nitric Oxide and of DETA NONOate in Arteriogenesis

Arteriogenesis: A focus on signal transduction cascades and transcription factors

Arginase inhibition attenuates arteriogenesis and interferes with M2 macrophage accumulation

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