Role of extracellular sulfate on vascular health

Principal Investigator

Scientific interest within the context of the graduate college:

Sulfate is an essential nutrient that supports numerous biological processes, including tissue development, cellular function, and overall physiological homeostasis. Its concentration in the body is tightly regulated by specialized sulfate transporters that mediate both dietary absorption and renal reabsorption. Despite its fundamental roles, the contribution of sulfate to vascular biology has been largely overlooked. Emerging evidence suggests that sulfate is critical for maintaining the structural and functional integrity of blood vessels, particularly through its incorporation into sulfated glycosaminoglycans, which are key components of the endothelial glycocalyx. We hypothesize that sulfate plays a vital role in preserving vascular integrity, supporting endothelial function, and regulating blood flow-domains that remain underexplored and represent significant knowledge gaps in biomedical research.

Project description:

We recently identified a subset of patients with impaired capacity to maintain normal blood sulfate concentrations due to damaging variants in the sulfate transporter geneSLC26A1.¹ These individuals present with musculoskeletal disorders, which we suspect are linked to systemic sulfate deficiency.² To investigate the underlying mechanisms, we developed a novel mouse model with tissue-specific deletion ofSLC26A1using Cre-Lox technology. Our findings indicate that global and kidney-specific deletion ofSLC26A1leads to significantly reduced plasma sulfate levels, primarily due to excessive urinary excretion. These mice also exhibit a skeletal phenotype characterized by impaired bone mineralization. To date, the vascular system has not been evaluated in this model. However, preliminary human data show that individuals carrying damagingSLC26A1variants exhibit increased cardiovascular mortality compared to matched controls, suggesting a potential vascular consequence of sulfate deficiency. This project seeks to fill this critical knowledge gap by exploring the relationship between extracellular sulfate levels and vascular health using complementary in vitro, in vivo, and population-based approaches.

Aim 1: Investigate the effects of low extracellular sulfate on vascular cell function in vitro. This aim will assess the impact of sulfate deficiency on endothelial and vascular smooth muscle cells, focusing on key parameters such as cell viability, nitric oxide signaling, glycocalyx integrity, and inflammatory response under defined culture conditions.

Aim 2: Evaluate vascular function in vivo in mice with deletion of SLC26A1. This aim will characterize vascular phenotypes in SLC26A1-deficient mice using histological, biochemical, and physiological assessments to determine whether systemic sulfate deficiency disrupts vascular structure and function.

Aim 3: Examine the association between damaging SLC26A1 variants and increased cardiovascular mortality in the Mayo Clinic Biobank. Leveraging data from the Mayo Clinic Biobank and the Tapestry Study, our current Re-Thinking Health student Felix Pitzken has identified that approximately 3% of over 150,000 individuals carry potentially damaging variants in SLC26A1. With support from our biostatistics team, this aim will evaluate whether these variants are associated with increased cardiovascular risk, and whether this risk is mediated by reduced plasma sulfate concentrations.

Application details

References