Targeting Anti-Angiogenic VEGF<sub>165</sub>b–VEGFR1 Signaling Promotes Nitric Oxide Independent Therapeutic Angiogenesis in Preclinical Peripheral Artery Disease Models
Nitric oxide (NO) is the critical regulator of VEGFR2-induced angiogenesis. Neither VEGF-A over-expression nor L-Arginine (NO-precursor) supplementation has been effective in helping patients with Peripheral Artery Disease (PAD) in clinical trials. One incompletely studied reason may be due to the p...
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MDPI AG
2022-08-01
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| author | Sivaraman Kuppuswamy Brian H. Annex Vijay C. Ganta |
| author_facet | Sivaraman Kuppuswamy Brian H. Annex Vijay C. Ganta |
| author_sort | Sivaraman Kuppuswamy |
| collection | DOAJ |
| description | Nitric oxide (NO) is the critical regulator of VEGFR2-induced angiogenesis. Neither VEGF-A over-expression nor L-Arginine (NO-precursor) supplementation has been effective in helping patients with Peripheral Artery Disease (PAD) in clinical trials. One incompletely studied reason may be due to the presence of the less characterized anti-angiogenic VEGF-A (VEGF<sub>165</sub>b) isoform. We have recently shown that VEGF<sub>165</sub>b inhibits ischemic angiogenesis by blocking VEGFR1, not VEGFR2 activation. Here we wanted to determine whether VEGF<sub>165</sub>b inhibition using a monoclonal isoform-specific antibody against VEGF<sub>165</sub>b vs. control, improved perfusion recovery in preclinical PAD models that have impaired VEGFR2-NO signaling, including (1) type-2 diabetic model, (2) endothelial Nitric oxide synthase-knock out mice, and (3) Myoglobin transgenic mice that have impaired NO bioavailability. In all PAD models, VEGF<sub>165</sub>b inhibition vs. control enhanced perfusion recovery, increased microvascular density in the ischemic limb, and activated VEGFR1-STAT3 signaling. In vitro, VEGF<sub>165</sub>b inhibition vs. control enhanced a VEGFR1-dependent endothelial survival/proliferation and angiogenic capacity. These data demonstrate that VEGF<sub>165</sub>b inhibition induces VEGFR1-STAT3 activation, which does not require increased NO to induce therapeutic angiogenesis in PAD. These results may have implications for advancing therapies for patients with PAD where the VEGFR2-eNOS-NO pathway is impaired. |
| first_indexed | 2024-03-10T01:57:19Z |
| format | Article |
| id | doaj.art-de1b4e0710294e768d98c29e0067d659 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T01:57:19Z |
| publishDate | 2022-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-de1b4e0710294e768d98c29e0067d6592023-11-23T12:55:05ZengMDPI AGCells2073-44092022-08-011117267610.3390/cells11172676Targeting Anti-Angiogenic VEGF<sub>165</sub>b–VEGFR1 Signaling Promotes Nitric Oxide Independent Therapeutic Angiogenesis in Preclinical Peripheral Artery Disease ModelsSivaraman Kuppuswamy0Brian H. Annex1Vijay C. Ganta2Vascular Biology Center and Department of Medicine, Augusta University, Augusta, GA 30912, USAVascular Biology Center and Department of Medicine, Augusta University, Augusta, GA 30912, USAVascular Biology Center and Department of Medicine, Augusta University, Augusta, GA 30912, USANitric oxide (NO) is the critical regulator of VEGFR2-induced angiogenesis. Neither VEGF-A over-expression nor L-Arginine (NO-precursor) supplementation has been effective in helping patients with Peripheral Artery Disease (PAD) in clinical trials. One incompletely studied reason may be due to the presence of the less characterized anti-angiogenic VEGF-A (VEGF<sub>165</sub>b) isoform. We have recently shown that VEGF<sub>165</sub>b inhibits ischemic angiogenesis by blocking VEGFR1, not VEGFR2 activation. Here we wanted to determine whether VEGF<sub>165</sub>b inhibition using a monoclonal isoform-specific antibody against VEGF<sub>165</sub>b vs. control, improved perfusion recovery in preclinical PAD models that have impaired VEGFR2-NO signaling, including (1) type-2 diabetic model, (2) endothelial Nitric oxide synthase-knock out mice, and (3) Myoglobin transgenic mice that have impaired NO bioavailability. In all PAD models, VEGF<sub>165</sub>b inhibition vs. control enhanced perfusion recovery, increased microvascular density in the ischemic limb, and activated VEGFR1-STAT3 signaling. In vitro, VEGF<sub>165</sub>b inhibition vs. control enhanced a VEGFR1-dependent endothelial survival/proliferation and angiogenic capacity. These data demonstrate that VEGF<sub>165</sub>b inhibition induces VEGFR1-STAT3 activation, which does not require increased NO to induce therapeutic angiogenesis in PAD. These results may have implications for advancing therapies for patients with PAD where the VEGFR2-eNOS-NO pathway is impaired.https://www.mdpi.com/2073-4409/11/17/2676angiogenesisanti-angiogenic VEGF-Aischemiagrowth factor signalingnitric oxidediabetes |
| spellingShingle | Sivaraman Kuppuswamy Brian H. Annex Vijay C. Ganta Targeting Anti-Angiogenic VEGF<sub>165</sub>b–VEGFR1 Signaling Promotes Nitric Oxide Independent Therapeutic Angiogenesis in Preclinical Peripheral Artery Disease Models Cells angiogenesis anti-angiogenic VEGF-A ischemia growth factor signaling nitric oxide diabetes |
| title | Targeting Anti-Angiogenic VEGF<sub>165</sub>b–VEGFR1 Signaling Promotes Nitric Oxide Independent Therapeutic Angiogenesis in Preclinical Peripheral Artery Disease Models |
| title_full | Targeting Anti-Angiogenic VEGF<sub>165</sub>b–VEGFR1 Signaling Promotes Nitric Oxide Independent Therapeutic Angiogenesis in Preclinical Peripheral Artery Disease Models |
| title_fullStr | Targeting Anti-Angiogenic VEGF<sub>165</sub>b–VEGFR1 Signaling Promotes Nitric Oxide Independent Therapeutic Angiogenesis in Preclinical Peripheral Artery Disease Models |
| title_full_unstemmed | Targeting Anti-Angiogenic VEGF<sub>165</sub>b–VEGFR1 Signaling Promotes Nitric Oxide Independent Therapeutic Angiogenesis in Preclinical Peripheral Artery Disease Models |
| title_short | Targeting Anti-Angiogenic VEGF<sub>165</sub>b–VEGFR1 Signaling Promotes Nitric Oxide Independent Therapeutic Angiogenesis in Preclinical Peripheral Artery Disease Models |
| title_sort | targeting anti angiogenic vegf sub 165 sub b vegfr1 signaling promotes nitric oxide independent therapeutic angiogenesis in preclinical peripheral artery disease models |
| topic | angiogenesis anti-angiogenic VEGF-A ischemia growth factor signaling nitric oxide diabetes |
| url | https://www.mdpi.com/2073-4409/11/17/2676 |
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