A limited role for regulatory T cells in post‐ischemic neovascularization

Hellingman, A.A.; Vlugt, Luciën E. P. M. van der; Lijkwan, Maarten A.; Bastiaansen, A.J.N.M.; Sparwasser, Tim; Smits, Hermelijn H.; Hamming, Jaap F.; Quax, Paul H.A.

doi:10.1111/j.1582-4934.2011.01300.x

Cited by 23 publications

(19 citation statements)

References 32 publications

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“…In PCAF −/− mice, we demonstrated decreased numbers of circulating leukocytes involved in arteriogenesis, like T cells 46 (predominantly activated CD4 + T cells 7, 11 ), natural killer cells 11 and regulatory T cells 9, 10 , and also in those cells that have not previously been implicated in arteriogenesis, including B cells. Furthermore, fewer dendritic cells were found in draining inguinal lymph nodes compared to WT mice, where the interaction between antigen-presenting dendritic cells and T cells takes place.…”

Section: Discussionmentioning

confidence: 74%

Lysine Acetyltransferase PCAF Is a Key Regulator of Arteriogenesis

Bastiaansen

Ewing

Boer

et al. 2013

ATVB

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Objective-Therapeutic arteriogenesis, that is, expansive remodeling of preexisting collaterals, using single-action factor therapies has not been as successful as anticipated. Modulation of factors that act as a master switch for relevant gene programs may prove more effective. Transcriptional coactivator p300-CBP-associated factor (PCAF) has histone acetylating activity and promotes transcription of multiple inflammatory genes. Because arteriogenesis is an inflammationdriven process, we hypothesized that PCAF acts as multifactorial regulator of arteriogenesis. Approach and Results-After induction of hindlimb ischemia, blood flow recovery was impaired in both PCAF −/− mice and healthy wild-type mice treated with the pharmacological PCAF inhibitor Garcinol, demonstrating an important role for PCAF in arteriogenesis. PCAF deficiency reduced the in vitro inflammatory response in leukocytes and vascular cells involved in arteriogenesis. In vivo gene expression profiling revealed that PCAF deficiency results in differential expression of 3505 genes during arteriogenesis and, more specifically, in impaired induction of multiple proinflammatory genes. Additionally, recruitment from the bone marrow of inflammatory cells, in particular proinflammatory Ly6C Bastiaansen et al PCAF Regulates Arteriogenesis 1903growth are multifactorial and too complex to be modulated by therapeutics that target a single gene or pathway. In contrast, modulation of a factor that acts as a master switch for multiple relevant gene programs may be a more effective strategy to augment arteriogenesis.A protein with such master switch potential is p300-CBPassociated factor (PCAF), a transcriptional coactivator with intrinsic histone acetyltransferase activity. PCAF acetylates histones H3 and H4, but there is also increasing evidence that PCAF modulates nonhistone proteins, [13][14][15][16] including hypoxiainducible factor 1α 17 and Notch. 18 Furthermore, the histone acetylating activity of PCAF is essential for nuclear factor κB (NF-κB)-mediated gene transcription 19 and facilitates inflammatory gene regulation. 20 Because arteriogenesis is an inflammatory-like process, we hypothesized that PCAF acts as master switch that stimulates multiple inflammatory processes important for collateral remodeling.Recently, it was shown in a large patient population study (>3000 individuals)21 that a variation in the promoter region of PCAF is associated with coronary heart disease-related mortality. 22 In support of this observation, we recently demonstrated a role for PCAF in vascular remodeling in a mouse model for reactive stenosis. However, whether PCAF participates in arteriogenesis has not yet been investigated.In the present study, we investigated the contribution of PCAF to postischemic neovascularization in a hindlimb ischemia (HLI) model, 23 using PCAF-deficient (PCAF −/− ) mice. When studying arteriogenesis in a knockout model, it is possible that the gene deletion may affect vascular development in the embryo, including collaterogenesis, thus affec...

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Section: Discussionmentioning

confidence: 74%

Lysine Acetyltransferase PCAF Is a Key Regulator of Arteriogenesis

Bastiaansen

Ewing

Boer

et al. 2013

ATVB

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“…Notably, several studies have indicated that type 1 T cells are more susceptible to Treg-mediated suppression than type 2 T lymphocytes [55]. However, Hellingman and coworkers recently reported only a mild inhibition of blood recovery in mice depleted of Tregs [56]. This suggests the possibility that augmented efficiency in blood flow recovery detected in CD28-deficient mice might be caused by intrinsic enhancement of type 1 responses.…”

Section: Reviewmentioning

confidence: 97%

Regulation of collateral blood vessel development by the innate and adaptive immune system

Sala

Pontecorvo

Agresta³

et al. 2012

Trends in Molecular Medicine

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“…Arteriogenesis is an inflammation-driven process [2], involving both the adaptive immune system (CD4 + T cells [3] [4], CD8 + T cells [5], regulatory T cells [6], [7]) and the innate immune system (monocytes [8]–[12], Toll-like receptors).…”

Section: Introductionmentioning

confidence: 99%

TLR4 Accessory Molecule RP105 (CD180) Regulates Monocyte-Driven Arteriogenesis in a Murine Hind Limb Ischemia Model

et al. 2014

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AimsWe investigated the role of the TLR4-accessory molecule RP105 (CD180) in post-ischemic neovascularization, i.e. arteriogenesis and angiogenesis. TLR4-mediated activation of pro-inflammatory Ly6Chi monocytes is crucial for effective neovascularization. Immunohistochemical analyses revealed that RP105+ monocytes are present in the perivascular space of remodeling collateral arterioles. As RP105 inhibits TLR4 signaling, we hypothesized that RP105 deficiency would lead to an unrestrained TLR4-mediated inflammatory response and hence to enhanced blood flow recovery after ischemia.Methods and ResultsRP105−/− and wild type (WT) mice were subjected to hind limb ischemia and blood flow recovery was followed by Laser Doppler Perfusion Imaging. Surprisingly, we found that blood flow recovery was severely impaired in RP105−/− mice. Immunohistochemistry showed that arteriogenesis was reduced in these mice compared to the WT. However, both in vivo and ex vivo analyses showed that circulatory pro-arteriogenic Ly6Chi monocytes were more readily activated in RP105−/− mice. FACS analyses showed that Ly6Chi monocytes became activated and migrated to the affected muscle tissues in WT mice following induction of hind limb ischemia. Although Ly6Chi monocytes were readily activated in RP105−/− mice, migration into the ischemic tissues was hampered and instead, Ly6Chi monocytes accumulated in their storage compartments, bone marrow and spleen, in RP105−/− mice.ConclusionsRP105 deficiency results in an unrestrained inflammatory response and monocyte over-activation, most likely due to the lack of TLR4 regulation. Inappropriate, premature systemic activation of pro-inflammatory Ly6Chi monocytes results in reduced infiltration of Ly6Chi monocytes in ischemic tissues and in impaired blood flow recovery.

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A limited role for regulatory T cells in post‐ischemic neovascularization

Cited by 23 publications

References 32 publications

Lysine Acetyltransferase PCAF Is a Key Regulator of Arteriogenesis

Lysine Acetyltransferase PCAF Is a Key Regulator of Arteriogenesis

Regulation of collateral blood vessel development by the innate and adaptive immune system

TLR4 Accessory Molecule RP105 (CD180) Regulates Monocyte-Driven Arteriogenesis in a Murine Hind Limb Ischemia Model

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