Hypertension is the single most important risk factor for global burden of disease, and significant percentages
of hypertension are attributed to alcohol consumption. While much focus has been placed on how alcohol
alters the neural, endocrine, and intrinsic cardiovascular mechanisms controlling blood pressure in rodents,
there is a significant gap in knowledge of how human resistance arteries are altered by chronic alcohol
consumption, both functionally and in terms of their underlying molecular composition. Interestingly, the
chaperone proteins known as sigma receptors-1 and -2 have been shown: 1) to be modulators of alcohol
drinking behavior in rodents, and 2) to also be abundantly expressed in vascular tissues, with the ability to alter
smooth muscle contraction. Thus, it is possible that drugs that modulate sigma receptor activity and reduce
alcohol intake in preclinical models may also provide the added benefit of accelerating the reversal of alcohol-
induced hypertension. On the other hand, because there is currently a significant gap in knowledge about the
specific role of sigma receptors in vascular functions, it is also possible that the advancement of novel
therapeutics targeting sigma receptors with the intention of reducing alcohol intake may in fact exacerbate
hypertension in alcoholics and limit the usefulness of this promising approach. With this in mind, the overall
objective of the current application is to determine the putative role of sigma receptors in alcohol-induced
hypertension. The central hypothesis is that chronic alcohol use promotes sigma-receptor-mediated
amplification of adrenergic receptor signaling in resistance arteries. The rationale for the proposed research is
that understanding of how chronic alcohol use impacts sigma receptor expression, signaling, and function in
resistance arteries would permit informed decisions about the safety of future therapeutic strategies targeting
sigma receptors to treat alcohol addiction. Guided by robust preliminary data, the central hypothesis will be
tested with two specific aims. Aim 1 is to determine the differential sigma receptor signaling in vascular smooth
muscle underlying changes in human resistance artery reactivity that accompany chronic alcohol use. Aim 2 is
investigate the alcohol-induced changes in vascular endothelial sigma receptor signaling. The experimental
endpoints will be functional reactivity of human mesenteric arteries obtained from organ donors, in the absence
and presence of sigma receptor modulators, correlated the de-identified donor histories of alcohol use and
other factors including sex and hypertension, plus proteomic trends and changes in noncoding RNAs that
occur in resistance arteries in relation to levels of alcohol use. The contribution of the proposed research will
be significant because it will provide the first direct evaluation of the impact of chronic alcohol use on the
intrinsic activity and proteomic composition of human resistance arteries. The proposed research is innovative
because it represents a substantial departure from the status quo of using rodents to study how chronic alcohol
use impacts vascular functions, while addressing the novel role of sigma receptors in vascular tissue.