angiogenesis

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Angiogenesis

VEGF-driven vascular recovery replacing flat-rate perfusion repair with hypoxia-dependent angiogenesis.

Biology

Angiogenesis during wound healing is driven by the HIF-1alpha/VEGF signaling axis. When tissue oxygen drops below a threshold, hypoxia-inducible factor 1-alpha (HIF-1alpha) stabilizes and induces vascular endothelial growth factor (VEGF) production. VEGF stimulates endothelial cell sprouting from intact capillaries at the wound margin, gradually restoring perfusion to the wound bed. M2 macrophages also produce VEGF, coupling immune resolution to vascular repair.

Angiogenesis consumes VEGF proportionally, providing negative feedback that prevents excessive vessel growth. In diabetic wounds, HIF-1alpha is impaired (Thangarajah et al. 2009), reducing VEGF production and delaying vascular recovery.

Model

VEGF PDE: diffusion 0.08, decay 0.01. Two sources:

• Hypoxia-driven: where O2 < vegf_hypoxia_threshold, VEGF is produced proportional to hypoxia severity (vegf_production_rate * (threshold - local_O2))
• M2 macrophages: m2_vegf_rate per M2 macrophage per step

Perfusion modulation: replaces the flat angio_rate in the perfusion module with angio_vegf_rate * local_vegf * demand, where demand is the deficit from healthy perfusion.

VEGF consumption: angiogenesis consumes VEGF at vegf_consumption_rate * recovery, providing negative feedback.

Feedback loop:

Wound --> Destroyed vessels --> Low perfusion --> Low O2
                                                    |
                                HIF-1alpha --> VEGF production
                           (diabetic: impaired)     |
                                VEGF --> Endothelial sprouting --> Perfusion recovery
                                                    |
                                VEGF consumed (negative feedback)
                                                    |
                      M2 Macrophages --> VEGF (immune-vascular coupling)

Parameters

From modules/angiogenesis/config.toml:

Parameter	Default	Units	Description	Source
enabled	true	bool	Master switch	Convention
vegf_diffusion	0.08	-	VEGF diffusion coefficient	Calibrated
vegf_decay	0.01	per step	VEGF natural decay	Calibrated
vegf_production_rate	0.002	per step	VEGF per hypoxic voxel	Johnson & Wilgus 2014 (DOI)
vegf_hypoxia_threshold	0.5	normalized	O2 for HIF-1alpha induction	Schugart et al. 2008 (DOI)
vegf_consumption_rate	0.1	fraction	VEGF consumed per unit recovery	Calibrated
angio_vegf_rate	0.01	per step	Perfusion recovery per unit VEGF	Flegg et al. 2012 (DOI)
m2_vegf_rate	0.001	per step	VEGF per M2 macrophage	Jetten et al. 2014 (DOI)

Coupling

Reads

Field	Source module	How used
O2	tissue	Hypoxia detection for VEGF production

Writes

Field	Consumer modules	What is written
VEGF	perfusion (modulates recovery rate)	VEGF concentration from hypoxia and M2 macrophages

Validation

Dataset	Observable	Sources	Notes
angiogenesis_parameters	VEGF dynamics, perfusion recovery coupling	Catrina 2004, Thangarajah 2009, Jetten 2014	Parameter derivation

Literature data

Reference curves for validation (full citations in SOURCES.yaml):

Dataset	File	Normalization
VEGF kinetics	vegf_kinetics.csv	Peak = 1.0

Metrics

Column	Units	Description
mean_vegf_wound	a.u.	Mean VEGF in wound

Source files

File	Purpose
vegf_pde.h	VEGF diffusion field with hypoxia source
vegf_op.h	VEGF-modulated perfusion recovery operation
config.toml	Module configuration