Endothelial dysfunction in human diabetic vascular complications: translating single-cell transcriptomics into...

Area of Science:

• Endothelial biology
• Vascular complications
• Genomics

Background:

• Type 2 diabetes mellitus (T2DM) is a systemic vascular disease.
• Endothelial cell (EC) dysfunction drives diabetic vascular complications (DVCs), leading to significant morbidity and mortality.
• Current therapies offer limited protection against microvascular and macrovascular injury, necessitating advanced vascular-targeted strategies.

Purpose of the Study:

• To synthesize human single-cell RNA sequencing studies of ECs in diabetic vasculature.
• To define mechanisms of EC dysfunction across different DVCs, including diabetic arteries, retinopathy, nephropathy, and foot ulcers.
• To propose a unifying framework for DVCs and inform novel therapeutic strategies.

Main Methods:

• Cross-tissue synthesis of human single-cell RNA sequencing data.
• Analysis of EC heterogeneity in diabetic arteries, retinopathy, nephropathy, and foot ulcers.
• Identification of tissue-specific endothelial states and regulatory programs.

Main Results:

• DVCs arise from tissue-specific EC state transitions driven by combined regulatory programs.
• Distinct EC states identified: pro-inflammatory/pro-fibrotic/anti-angiogenic (arteries), pathological angiogenic/inflammatory (retinopathy), pro-fibrotic/maladaptive angiogenic (nephropathy), inflammatory/anti-angiogenic (foot ulcers).
• Limited efficacy of single-pathway therapies (e.g., VEGF-centered) explained; VEGF-independent mechanisms identified.

Conclusions:

• A unifying framework posits DVCs result from complex, tissue-specific EC state transitions.
• Combination therapies targeting multiple regulatory layers within specific EC states are proposed.
• A paradigm shift towards vascular bed-specific, combinatorial, and state-directed therapies for EC dysfunction in DVCs is supported.