A Special Report on the NHLBI Initiative to Study Cellular and Molecular Mechanisms of Arterial Stiffness and Its Association With Hypertension

Abstract

Large arteries (especially the aorta) lose elasticity and thicken with aging and as a consequence of other conditions, thus leading to central arterial stiffening and associated adverse effects on blood flow and pressure. Arterial stiffness can be defined and measured in different ways, at a local level or systemically. Increases in either the intrinsic (material) stiffness or net structural (combined geometric and material) arterial stiffness, or both, can increase the velocity at which the pressure pulse travels along the arterial tree and central pulse pressure, which can negatively impact downstream resistance vessels and organs (i.e., heart, brain and kidney). Clarifying temporal and causal relationships between arterial stiffening and hypertension was identified by NHLBI as an important gap of knowledge, with a potential for clinical translation. NIH-funded studies, more than half of them supported by the NHLBI (Online Figure), have investigated various aspects of arterial stiffening in humans and in experimental models. To enable a more focused research effort on this topic, NHLBI launched a Request for Applications (RFA) HL-10-027, entitled “Cellular and Molecular Mechanisms of Arterial Stiffening and Its Relationship to Development of Hypertension (R01).” This initiative supported 11 R01 awards during 2010–2015 (Online Table I; cumulative ~$20 million dollars in total costs), which represented a significant component of the overall NHLBI investment in this field. Here we report a summary of important scientific findings that resulted from this NHLBI-initiated research effort, constituting the basis of more than 200 original research and review articles (Online Table II), some highlighted here, many conference presentations, and several patents.

Keywords: aorta; blood pressure; cardiovascular disease; elasticity; hypertension.

Figure A. simplified model relating arterial stiffness and hypertension

Aging and various human disorders can lead to endothelial dysfunction and smooth muscle cell (SMC) phenotype changes (e.g., from contractile to synthetic) and then lead to increased arterial stiffness. As discussed in the text, various cellular and molecular mechanisms involving multiple genes and signaling pathways are likely involved during the process of arterial stiffening. Depending on the condition (or stage), some modifiers such as exercise, weight loss, and/or diet may be able to reverse arterial stiffness and lower blood pressure. The importance of blood pressure control is emphasized by the insidious positive feedback-loop between increased arterial stiffness and high blood pressure. Due to incomplete understanding of causality between arterial stiffness and high blood pressure in different conditions, a question mark is placed alongside the arrows.