# Serotonin receptor contribution to inflammation-induced calcific aortic valve disease

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2021 · $390,000

## Abstract

PROJECT SUMMARY/ABSTRACT
No pharmacological approach has been found to prevent/treat calcific aortic valve disease (CAVD), whose
pathophysiological changes include calcification and fibrosis, causing aortic stenosis, often in combination with
regurgitation. Evidence shows that pro-inflammatory cytokines are potent stimulators of cardiovascular
calcification, while the serotonergic system is a potent stimulator of fibrosis. In particular, serotonin receptor 2B
(SR-2B) activation is known to cause structural and mechanical changes in aortic valves, such as fibrosis and
thickening, in some cases, dense nodules, though not calcification. Clinical studies also show that serotonin (5-
HT) levels are almost twice as high in patients with aortic stenosis, and are significantly associated with
progression of aortic stenosis. These findings suggest that SR-2B activation also contributes to the
pathogenesis of inflammation-induced CAVD. Interestingly, as confirmed in our preliminary studies, the
predominant receptor subtype expressed in murine aortic valve interstitial cells, at baseline, is SR-2A, rather
than SR-2B. However, in our additional preliminary studies, we found that it was SR-2B that was dramatically
upregulated (> 30-fold) by TNF-a. This induction required BMP-2 signaling and may account for our findings
that, although 5-HT augmented TNF-a-induced calcification, it had no effect alone.. We also found that the
TNF-a/5-HT-induced calcification occurred via induction of Orai1, a plasma membrane calcium channel, and
this calcification was attenuated by specific inhibitors or knockdown of only SR-2B. Additional preliminary
studies show that circulating peripheral 5-HT levels were higher in hyperlipidemic (Apoe-/-) compared with wild
type mice, and SR-2B expression in the valve cusps was adjacent to cholesterol clefts and calcified lesions in
Apoe-/- but not in wild type mice. Based on the collective evidence, we hypothesize that 5-HT in the
hyperlipidemic milieu plays a key role in CAVD. We posit that hyperlipidemia increases circulating levels of
both 5-HT and inflammatory cytokines, the latter of which induce SR-2B and osteogenesis in valve cusps, and,
together, these events lead to CAVD. In Aim 1, we will determine receptor subtype-specific effects of 5-HT
on matrix mechanics under non-inflammatory (SR-2A dominant) as well as on calcification under inflammatory
(SR-2B dominant) conditions and on the signaling pathways mediating TNF-a induction of SR-2B and of
downstream osteoblastic differentiation. In Aim 2, we will determine whether 5-HT signaling via SR-2B is
critical for inflammation-induced CAVD using 1) a 5-HT-deficient, inflammatory mouse model (Tph1-/-Ldlr-/-
Apob100/100), and 2) receptor subtype-specific agonists and antagonists. We will apply cutting edge technology,
including laser light sheet fluorescence microscopy; serial in vivo fused 18F-µPET-µCT imaging; atomic force
microscopy; 3-D hydrogel cultures; and implantation of receptor...

## Key facts

- **NIH application ID:** 10124425
- **Project number:** 5R01HL137647-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Linda L. Demer
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $390,000
- **Award type:** 5
- **Project period:** 2019-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10124425

## Citation

> US National Institutes of Health, RePORTER application 10124425, Serotonin receptor contribution to inflammation-induced calcific aortic valve disease (5R01HL137647-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10124425. Licensed CC0.

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