Background/Rationale: Angiogenesis - formation of new capillary blood vessels is a fundamental process essential for healing of tissue injury, e.g. gastric erosions (GE) and ulcers (GU). Gastric mucosa of aging humans and rats (aging gastric mucosa) exhibits increased susceptibility to injury, impaired angiogenesis and delayed healing. [Our overall hypothesis is that nerve growth factor (NGF) is critical for gastric endothelial cell (EC) viability, function, angiogenesis and GU healing, and that NGF deficiency in aging ECs is the major mechanism of aging-related impairment of gastric angiogenesis and GU healing in aging individuals.] The rationale for this hypothesis stems from our preliminary studies showing that: 1) aging gastric ECs (AGECs) have reduced expression of NGF, and NGF protein and/or NGF gene therapy restores in vitro angiogenesis in aging ECs cells and reverses NSAIDs-induced inhibition of angiogenesis, and [2) local treatment of GU in aging rats with NGF significantly increases local expression of NGF and VEGF, angiogenesis, accelerates ulcer healing, and improves mucosal regeneration.] Our specific objectives are to determine whether and to what extent: 1) NGF and its signaling are critical for gastric ECs viability, function and angiogenesis and to identify the underlying molecular mechanisms; 2) NGF deficiency is: (a) crucial mechanism for ECs' aging and for aging-related impairment of EC proliferation and angiogenesis and (b) whether NGF treatment or NGF gene therapy restores in vitro angiogenesis in aging ECs; [3) Local treatment of GUs in aging rats with NGF will improve vascular regeneration and GU healing and whether these events can be visualized in vivo and in real time using confocal laser endomicroscopy (CLE).] Our long-term objective is to uncover novel mechanisms that regulate gastric angiogenesis and its impairment in aging, to provide a basis for the therapeutic use of NGF to improve angiogenesis and healing of GU in aging individuals and to use CLE for in vivo assessment of GU healing, vascular regeneration and for identifying GU scar abnormalities that may be the basis for the ulcer recurrence. Design: Since ECs are critical targets and effectors of angiogenesis, in in vitro studies in ECs isolated from gastric mucosa of young and aging rats we will determine the mechanisms underlying aging related impairment of EC functions, expression of NGF, VEGF, their receptors, PI3K/Akt and MAPK signaling, and the role of NGF in EC survival, migration, proliferation and angiogenesis. Next we will examine in vivo in aging and young rats sequential events of GU healing and vascular regeneration and will determine whether locally injected NGF will improve GU healing in aging rats and prevent NSAIDs-induced GU recurrence. We will also determine human relevance of our experimental findings using human specimens of GUs from young and aging individuals. Significance: The central topic of our project is neovascularization, injury healing and impact of aging. In 2006, ~39 million Americans (12% of population) were 65 years of age or older, and this number is projected to reach ~70 million by 2030. This population is at high risk of tissue and organ injuries, and GU complications. Impaired angiogenesis in aging is a key factor in delayed healing, morbidity and mortality. [Recent studies indicate that the incidence of non-H. pylori, non-NSAIDs ulcers (idiopathic ulcers) is increasing and they constitute up to 30% of all ulcers and patients with a history of idiopathic bleeding ulcers have a high risk of recurrent ulcer bleeding and a high mortality 83 - 92%. Therefore the GU recurrence and its complications still remain important clinical issue, especially in aging and severely ill patients.] The proposed studies will provide insight into novel mechanisms and the regulatory role of NGF and angiogenesis in GU healing and their relation to aging-related impairment of these processes. This novel information can be applicable to other areas of mucosal healing including inflammatory bowel disease, esophageal erosions and ulcers, as well as to cancer-related neovascularization.

Public Health Relevance

Gastric injury-erosive gastritis and gastric ulcers are frequently encountered in VA patients often as a result chronic NSAIDs use for arthritis, pain or other ailments. Patients over 65 years of age have significantly increased gastric mucosal injury and have 8-fold increased risk of gastric ulcer complications than younger patients. Aging gastropathy is a clinically important issue, especially since the aging US population is rapidly growing and it is estimated that by the year 2030, about 70 million Americans will be over 65 years of age. Lifetime prevalence of gastric ulcers in the US population is about 5% and their incidence among Veterans is 2.5-fold higher posing a significant economic impact to the VA. Impaired neovascularization is the key factor in delayed tissue injury healing, morbidity, and mortality. [The central topic of our proposed research is directly related to regeneration of blood vessels, gastric ulcer healing, role of aging new mechanisms and application of newest CLE technology to evaluate healing.]

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX000626-08
Application #
9605165
Study Section
Surgery (SURG)
Project Start
2009-10-01
Project End
2019-09-30
Budget Start
2018-10-01
Budget End
2019-09-30
Support Year
8
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Veterans Health Administration
Department
Type
DUNS #
625399951
City
Long Beach
State
CA
Country
United States
Zip Code
90822
Ahluwalia, Amrita; Jones, Michael K; Hoa, Neil et al. (2018) Reduced NGF in Gastric Endothelial Cells Is One of the Main Causes of Impaired Angiogenesis in Aging Gastric Mucosa. Cell Mol Gastroenterol Hepatol 6:199-213
Ahluwalia, Amrita; Brzozowska, Iwona M; Hoa, Neil et al. (2018) Melatonin signaling in mitochondria extends beyond neurons and neuroprotection: Implications for angiogenesis and cardio/gastroprotection. Proc Natl Acad Sci U S A 115:E1942-E1943
Ahluwalia, A; Brzozowski, T; Jones, M K et al. (2017) Formation of new blood vessels during gastric ulcer healing. Role of bone marrow derived endothelial progenitor cells. J Physiol Pharmacol 68:585-589
Ahluwalia, Amrita; Jones, Michael K; Hoa, Neil et al. (2017) NGF protects endothelial cells from indomethacin-induced injury through activation of mitochondria and upregulation of IGF-1. Cell Signal 40:22-29
Ahluwalia, Amrita; Jones, Michael K; Brzozowski, Tomasz et al. (2016) Nerve growth factor is critical requirement for in vitro angiogenesis in gastric endothelial cells. Am J Physiol Gastrointest Liver Physiol 311:G981-G987
Tarnawski, A S; Ahluwalia, A; Jones, M K et al. (2016) Expression of nerve growth factor in rat stomach. Implications for interactions between endothelial, neural and epithelial cells. J Physiol Pharmacol 67:879-883