Syndecan-4 proteoliposomes enhance revascularization in a rabbit hind limb ischemia model of peripheral ischemia

Sligar, Andrew D.; Howe, Gretchen; Goldman, Julia; Felli, Patricia; Gómez-Hernández, Almudena; Takematsu, Eri; Veith, Austin; Desai, Shubh; Riley, William J.; Singeetham, Rohan; Lei, Mei-Guey; Callahan, Gregory; Ashirov, David; Smalling, Richard W.; Baker, Aaron

doi:10.1016/j.actbio.2023.06.006

Cited by 2 publications

(11 citation statements)

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“…The studies performed were in accordance with ARRIVE guidelines. The model was performed as described in our previous studies in which we optimized the model for reduced recovery from ischemia 28 , 29 . New Zealand rabbits (male; 4–6 months of age; Charles River, Inc.) were transitioned from standard alfalfa chow to a 0.1% cholesterol diet over the course of five days.…”

Section: Methodsmentioning

confidence: 99%

“…To limit pain and risk of infection, buprenorphine (0.01 mg/kg) and Baytril (5 mg/kg) were administered using a subcutaneous injection with a 25G needle. Further details of the procedure can be found in our previous publications 28 , 29 . To induce ischemia in the hind limb of New Zealand rabbits, a longitudinal incision was made in the skin over the femoral artery.…”

Section: Methodsmentioning

confidence: 99%

“…The injections were placed evenly along both sides of the femoral artery on the thigh. To achieve uniform injections, a silicone sheet with holes to guide the injection was used 28 , 29 . Treatments included tmSCF nanodiscs in alginate and an alginate-only control.…”

Section: Methodsmentioning

confidence: 99%

“…Treatments included tmSCF nanodiscs in alginate and an alginate-only control. At the study endpoint, angiograph was performed, the animals were euthanized and pressure perfused as described in our previous studies 28 , 29 .…”

Section: Methodsmentioning

confidence: 99%

“…For peripheral ischemia, rabbits are typically used as the precursor to human studies for treating PAD due the well-developed musculature of the lower limb. Our group recently developed an optimized rabbit model of hindlimb ischemia that includes hyperlipidemia and diabetes 28 , 29 . A major advantage of this model is that it exhibits resistance to angiogenic therapies and longer-term ischemia, similar to human patients, in contrast to health rabbit models that revascularize more quickly and have been found to correlate poorly to outcomes in clinical trials.…”

Section: Introductionmentioning

confidence: 99%

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Transmembrane stem factor nanodiscs enhanced revascularization in a hind limb ischemia model in diabetic, hyperlipidemic rabbits

Takematsu,

Massidda,

Howe

et al. 2024

Sci Rep

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Therapies to revascularize ischemic tissue have long been a goal for the treatment of vascular disease and other disorders. Therapies using stem cell factor (SCF), also known as a c-Kit ligand, had great promise for treating ischemia for myocardial infarct and stroke, however clinical development for SCF was stopped due to toxic side effects including mast cell activation in patients. We recently developed a novel therapy using a transmembrane form of SCF (tmSCF) delivered in lipid nanodiscs. In previous studies, we demonstrated tmSCF nanodiscs were able to induce revascularization of ischemia limbs in mice and did not activate mast cells. To advance this therapeutic towards clinical application, we tested this therapy in an advanced model of hindlimb ischemia in rabbits with hyperlipidemia and diabetes. This model has therapeutic resistance to angiogenic therapies and maintains long term deficits in recovery from ischemic injury. We treated rabbits with local treatment with tmSCF nanodiscs or control solution delivered locally from an alginate gel delivered into the ischemic limb of the rabbits. After eight weeks, we found significantly higher vascularity in the tmSCF nanodisc-treated group in comparison to alginate treated control as quantified through angiography. Histological analysis also showed a significantly higher number of small and large blood vessels in the ischemic muscles of the tmSCF nanodisc treated group. Importantly, we did not observe inflammation or mast cell activation in the rabbits. Overall, this study supports the therapeutic potential of tmSCF nanodiscs for treating peripheral ischemia.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Transmembrane stem factor nanodiscs enhanced revascularization in a hind limb ischemia model in diabetic, hyperlipidemic rabbits

Takematsu,

Massidda,

Howe

et al. 2024

Sci Rep

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Pro-angiogenic Terbium Hydroxide Nanorods Improve Critical Limb Ischemia in Part by Amelioration of Ischemia-Induced Endothelial Injury

Basuthakur,

Roy,

Ghosh

et al. 2024

ACS Appl. Bio Mater.

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Critical limb ischemia (CLI) refers to a severe condition resulting from gradual obstruction in the supply of blood, oxygen, and nutrients to the limbs. The most promising clinical solution to CLI is therapeutic angiogenesis. This study explored the potency of pro-angiogenic terbium hydroxide nanorods (THNR) for treatment of CLI, with a major focus on their impact on ischemia-induced maladaptive alterations in endothelial cells as well as on vascularization in ischemic limbs. This study demonstrated that, in hypoxia-exposed endothelial cells, THNR improve survival and promote proliferation, migration, restoration of nitric oxide production, and regulation of vascular permeability. Based on molecular studies, these attributes of THNR can be traced to the stimulation of PI3K/AKT/eNOS signaling pathways. Besides, Wnt/GSK-3β/β-catenin signaling pathways may also play a role in the therapeutic actions of THNR. Furthermore, in the murine model of CLI, THNR administration can integrally re-establish blood perfusion with concomitant reduction of muscle damage and inflammation. Additionally, improvement of locomotor activities and motor coordination in ischemic limbs in THNR treated mice is also evident. Overall, the study demonstrates that THNR have the potential to be developed as an efficacious and cost-effective alternative clinical therapy for CLI, using a nanomedicine approach.

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Syndecan-4 proteoliposomes enhance revascularization in a rabbit hind limb ischemia model of peripheral ischemia

Cited by 2 publications

References 61 publications

Transmembrane stem factor nanodiscs enhanced revascularization in a hind limb ischemia model in diabetic, hyperlipidemic rabbits

Transmembrane stem factor nanodiscs enhanced revascularization in a hind limb ischemia model in diabetic, hyperlipidemic rabbits

Pro-angiogenic Terbium Hydroxide Nanorods Improve Critical Limb Ischemia in Part by Amelioration of Ischemia-Induced Endothelial Injury

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