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As Taiwan enters a super-aged society, cardiovascular disease is no longer merely a problem of repair, but of sustainability—how long vascular systems can function without repeated hospitalization. This talk argues that the answer lies not in large vessels alone, but fundamentally in the microvasculature.

Drawing from clinical observations, experimental models, and human single-cell transcriptomic data, I will demonstrate that sex is not a confounding variable in vascular disease, but a core biological signal that critically shapes vascular aging and repair. Historical concepts such as the Yentl Syndrome highlight how sex-specific cardiovascular differences have been recognized for decades, yet remain insufficiently resolved in both research design and clinical practice. Our work reveals that male and female vasculature employ distinct repair strategies following injury, differences that persist even after hormonal decline with aging. This led us to identify SIRT1, a longevity-associated gene, as a key intersection linking sex, aging, and vascular resilience. Using aortic dissection models, retinal microvasculature, and single-cell RNA sequencing of human specimens, we identify pericytes as a central but previously underappreciated regulator of vascular stability. Female tissues exhibit higher pericyte abundance, enhanced cytoskeletal remodeling programs, and superior microvascular integrity. In contrast, male tissues show reduced pericyte coverage, increased fibrosis, and vulnerability to collapse. Beyond vascular disease, we demonstrate that SIRT1-dependent pericyte dysfunction increases blood–brain barrier permeability, facilitating brain metastasis, and contributes to doxorubicin-induced cardiotoxicity. Remarkably, activated pericytes form tunneling nanotubes capable of directly transporting angiogenic factors such as VEGF, revealing a previously unknown mechanism of cell-intrinsic vascular repair and therapeutic delivery.

In conclusion, this lecture proposes a paradigm shift: sex-aware, microvascular-centered precision medicine is essential for addressing aging-related diseases. By redefining sex as biological signal rather than experimental noise, and pericytes as active therapeutic agents rather than passive support cells, we aim to outline a future blueprint for predictive, resilient, and minimally invasive vascular medicine in an aging society.