eprintid: 36479
rev_number: 15
eprint_status: archive
userid: 8752
dir: disk0/00/03/64/79
datestamp: 2025-04-30 08:01:33
lastmod: 2025-05-30 09:05:55
status_changed: 2025-04-30 08:01:33
type: doctoralThesis
metadata_visibility: show
creators_name: Abouissa, Aya
title: Dynamic Endothelial Cell-Driven Cross-Talk in Response to Neonatal vs. Adult Cardiac Pressure Overload:
Unraveling Compensatory and Maladaptive Mechanisms
subjects: ddc-000
divisions: i-140001
divisions: i-60210
divisions: i-65000
adv_faculty: af-14
abstract: Background: Cardiac pressure overload (PO) is a common detrimental stimulus triggering pathological cardiac remodeling and heart failure (HF) in adult patients, mainly secondary to aortic valve stenosis or chronic arterial hypertension. Despite modern and advanced therapeutic options, HF remains the leading cause of high mortality worldwide. The paucity of regeneration in the adult mammalian heart in response to injury is a key therapeutic barrier in cardiovascular medicine. Upon PO, the adult murine myocardium undergoes significant pathological remodeling, hallmarked by capillary rarefaction, enhanced myocardial apoptosis and interstitial fibrosis. In contrast, our group has previously shown that the neonatal murine heart retains a transient regenerative window during the first postnatal week when subjected to neonatal transverse aortic constriction (nTAC), an in-vivo murine model of PO induction through aortic ligation in neonates. One-day old mice (P1) hearts exposed to nTAC completely adapt in response to injury and maintain cardiac function with minimal signs of myocardial fibrosis. However, nTAC in P7 mice leads to HF. A major contributor to full heart regeneration and adaptation in P1 mice is the rapid and enhanced heart revascularization through angiogenesis in response to nTAC, while this capacity is significantly diminished in P7 mice.
Hypothesis: A highly synchronized endothelial-derived intercellular communication between the different cell compartments of the heart is hypothesized in response to PO, to prevent the shift from the compensatory phenotype observed in P1 mice, to the development of cardiac maladaptation in P7 and adult mice.
Methods: For this purpose, bulk RNA sequencing was first utilized to determine the RNA transcriptomic changes in endothelial cells (ECs) during subacute and chronic phases of PO in adult mice. Additionally, in neonatal mice, single-cell RNA sequencing was used to identify EC sub-populations that play a key role in the transition from an adaptive to a maladaptive response to nTAC. EC-secreted ligands specific to each surgical time point were identified, and their potential autocrine and paracrine effects were analyzed in vitro.
Results: Upon PO induction in adult mice, my experiments show that ECs transiently express collagen and matrix remodeling genes, along with cell cycle-related genes, during the initial short-term response to the surgery. In addition, the upregulation of inflammatory genes by ECs peaked during the subacute phase of PO and remained elevated throughout the chronic stage. Intercellular communication of these EC-secreted matrix proteins triggered cardiomyocytes’ hypertrophy, ECs proliferation and migration, along with fibroblasts’ migration.
On the other hand, endothelial cells that I isolated from neonatal murine hearts, which exhibit an adaptive response to nTAC, enriched certain EC subpopulations linked to vasculature development and sprouting angiogenesis. Upon analysis, I could identify three interesting EC-secreted ligands. In direct cell contact 2D and 3D co-culture models, overexpression of these candidates in ECs enhanced cardiomyocytes’ proliferation and cytokinesis as well as maintained proper cardiomyocyte’s contraction. On the contrary, the downregulation of these genes in ECs lead to an opposite maladaptive phenotype in cardiomyocytes.
Conclusion: Conclusively, my work shows that cardiac ECs exhibit a great age- and timepoint-specific dynamic plasticity in response to PO. These observations might shed light on the potential crucial role of EC-derived angiocrine factors in promoting compensatory mechanisms to cardiac pressure overload.
date: 2025
id_scheme: DOI
id_number: 10.11588/heidok.00036479
ppn_swb: 1927183898
own_urn: urn:nbn:de:bsz:16-heidok-364790
date_accepted: 2024-12-13
advisor: HASH(0x55caa0db66f8)
language: eng
bibsort: ABOUISSAAYDYNAMICEND20241213
full_text_status: public
place_of_pub: Heidelberg
citation:   Abouissa, Aya  (2025) Dynamic Endothelial Cell-Driven Cross-Talk in Response to Neonatal vs. Adult Cardiac Pressure Overload: Unraveling Compensatory and Maladaptive Mechanisms.  [Dissertation]     
document_url: https://archiv.ub.uni-heidelberg.de/volltextserver/36479/1/AyaAbouissa_Dissertation_HBIGS_13Dec2024.pdf