Role of lipoma-preferred partner in the phenotype control of vascular smooth muscle cells in the face of hypertension

Introduction: Hypertension continues to be one of the main causes of death worldwide contributing to ischemic heart disease, stroke, and renal pathologies. Chronically elevated blood pressure induces an extensive arterial wall remodeling process as a response to increased wall stress. Lipoma preferred partner (LPP), a Lin11–Isl1–Mec3 (LIM)-domain protein, is involved in sensing and/or transducing this mechanical cue. LPP is primarily expressed by vascular smooth muscle cells (VSMCs) and seems to maintain the quiescent contractile phenotype of these cells, whereby its exact mechanism of action as well as its role in hypertension remain indistinct. Methods and Results: In a mouse model of hypertension, LPP-deficient (LPP-KO) animals showed no signs of cardiac dysfunction, but presented with strong vascular pathologies. These include aortic intramural hematoma as well as ruptures resulting in a high premature mortality amongst male but not female mice. To investigate their ability to adapt to changes in blood pressure, isolated mesenteric artery segments from these mice were perfused in a myograph, where they showed an inherently reduced myogenic response. Concordantly, in 2D and 3D functional assays, primary aortic LPP-KO VSMCs displayed higher rates of proliferation and motility but lower contractility compared to control cells. To gain more in-depth mechanistic insight, VSCMs were exposed to cyclic stretch followed by bulk RNA-sequencing analysis according to which LPP-KO VSMCs reveal a prominent pro-inflammatory gene expression profile. To further support these findings, publicly available single-cell RNA sequencing data of vascular cells from patients with or without aortic aneurysms were re-analyzed. This data show that the expression of LPP is significantly lower in aneurysm as compared to control vessel specimens. Moreover, subclustering of the data indicates that LPP mRNA levels are significantly lower in human VSMCs with an activated synthetic phenotype, compared to cells with a quiescent contractile phenotype, regardless of the presence of an aneurysm or not. Conclusion: Overall, our data indicate an important role of LPP in VSMC phenotype control as well as in the adaptation of the vascular wall to hypertension, i.e. increased wall stress. This work was supported by a grant from Deutsche Forschungsgemeinschaft to MarkusHecker (HE 1587/12-2) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.